Alternative titles; symbols
HGNC Approved Gene Symbol: CFTR
SNOMEDCT: 190905008; ICD10CM: E84, E84.9; ICD9CM: 277.0;
Cytogenetic location: 7q31.2 Genomic coordinates (GRCh38): 7:117,480,025-117,668,665 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.2 | {Bronchiectasis with or without elevated sweat chloride 1, modifier of} | 211400 | Autosomal dominant | 3 |
| {Hypertrypsinemia, neonatal} | 3 | |||
| {Pancreatitis, hereditary} | 167800 | Autosomal dominant | 3 | |
| Congenital bilateral absence of vas deferens | 277180 | Autosomal recessive | 3 | |
| Cystic fibrosis | 219700 | Autosomal recessive | 3 | |
| Sweat chloride elevation without CF | 3 |
The CFTR gene encodes an ATP-binding cassette (ABC) transporter that functions as a low conductance Cl(-)-selective channel gated by cycles of ATP binding and hydrolysis at its nucleotide-binding domains (NBDs) and regulated tightly by an intrinsically disordered protein segment distinguished by multiple consensus phosphorylation sites termed the regulatory domain (summary by Wang et al., 2014).
Riordan et al. (1989) isolated overlapping cDNA clones from epithelial cell libraries with a genomic DNA segment containing a portion of the putative gene causing cystic fibrosis (CF; 219700). Transcripts approximately 6,500 nucleotides in size were detectable in the tissues affected in patients with CF. The predicted protein consists of 2 similar motifs, each with a domain having properties consistent with membrane-association, and a domain believed to be involved in ATP binding. In CF patients, a deleted phenylalanine residue occurs at the center of the putative first nucleotide-binding fold (NBF). The predicted protein has 1,480 amino acids with a molecular mass of 168,138 Da. The characteristics are remarkably similar to those of the mammalian multidrug resistant P-glycoprotein (171050), which also maps to 7q, and to a number of other membrane-associated proteins. To avoid confusion with the previously named CF antigen (123885), Riordan et al. (1989) referred to the protein as cystic fibrosis transmembrane conductance regulator (CFTR).
Cystic fibrosis represents the first genetic disorder elucidated strictly by the process of reverse genetics (later called positional cloning), i.e., on the basis of map location but without the availability of chromosomal rearrangements or deletions such as those that have greatly facilitated previous success in the cloning of human disease genes in Duchenne muscular dystrophy (310200), retinoblastoma (180200), and chronic granulomatous disease (306400), for example. By use of a combination of chromosome walking and jumping, Rommens et al. (1989) succeeded in covering the CF region on 7q. The jumping technique was particularly useful in bypassing 'unclonable' regions, which are estimated to constitute 5% of the human genome. (Yeast artificial chromosome (YAC) vectors represent an alternative strategy.) The identification of undermethylated CpG islands was 1 tip-off; another was screening of a cDNA library constructed from cultured sweat gland cells of a non-CF individual. The CF gene proved to be about 250,000 bp long, a surprising finding since the absence of apparent genomic rearrangements in CF chromosomes and the evidence of a limited number of CF mutations predicted a small mutational target.
Green and Olson (1990) described a general strategy for cloning and mapping large regions of human DNA with yeast artificial chromosomes (YACs). By analyzing 30 YAC clones from the region of chromosome 7 containing the CFTR gene, a contig map spanning more than 1.5 Mbp was assembled. Individual YACs as large as 790 kb and containing the entire CF gene were constructed in vivo by meiotic recombination in yeast between pairs of overlapping YACs. Anand et al. (1991) described the physical mapping of a 1.5-Mbp region encompassing 2 genetic loci flanking the CF locus and contained within a series of YAC clones. The entire CFTR gene was included within 1 of these YACs, a 310-kb clone also containing flanking sequence in both the 5-prime and 3-prime directions from the gene.
Riordan et al. (1989) identified 24 exons in the CFTR gene.
With the hope of identifying conserved regions of biologic interest by sequence comparison, Ellsworth et al. (2000) sought to establish the sequence of the chromosomal segments encompassing the human CFTR and mouse Cftr genes. Bacterial clone-based physical maps of the relevant human and mouse genomic regions were constructed, and minimally overlapping sets of clones were selected and sequenced. Analyses of the resulting data provided insights about the organization of the CFTR/Cftr genes and potential sequence elements regulating their expression.
Riordan et al. (1989) mapped the CFTR gene to chromosome 7q. For additional information on the mapping of the gene for cystic fibrosis, see 219700.
The mapping of the murine equivalent of the WNT2 and MET (164860) genes to mouse chromosome 6 (Chan et al., 1989) strongly indicated that the mouse equivalent of the cystic fibrosis gene is also located on chromosome 6. By Southern analysis of mouse/Chinese hamster somatic cell hybrid DNAs, Kelley et al. (1992) mapped the Cftr gene to chromosome 6. Using restriction fragment length variants (RFLVs) in the study of interspecific backcrosses, Siegel et al. (1992) demonstrated that the Cftr gene in the mouse is close to Met and Cola-2. Trezise et al. (1992) demonstrated that the Cftr locus is on rat chromosome 4. Study of other loci suggested that an ancestral mammalian chromosome is represented by the present-day rat chromosome 4: 5 genes are syntenic on rat chromosome 4 and mouse chromosome 6 but are divided between human chromosomes 7 and 12. Another 5 genes that are syntenic on rat chromosome 4 and human chromosome 7 are divided between chromosomes 5 and 6 in the mouse.
In addition to functioning as a chloride channel, CFTR controls the regulation of other transport pathways. For example, patients with CF and the homozygous CFTR-deficient mouse have enhanced sodium ion absorption; this enhanced sodium ion absorption is corrected by addition of a wildtype copy of CFTR. CFTR and outwardly rectifying chloride channels (ORCCs) are distinct channels but are linked functionally via an unknown regulatory mechanism. Schwiebert et al. (1995) presented results from whole-cell and single-channel patch-clamp recordings, short-circuit current recordings, and ATP-release assays of normal, CF, and wildtype or mutant CFTR-transfected CF airway cultured epithelial cells indicating that CFTR regulates ORCCs by triggering the transport of the potent agonist, ATP, out of the cell. The results suggested that CFTR functions to regulate other chloride ion secretory pathways in addition to conducting chloride ion itself.
A quality control system that rapidly degrades abnormal membrane and secretory protein is stringently applied to the CFTR protein; approximately 75% of the wildtype precursor and 100% of the delF508 variant (602421.0001) are rapidly degraded before exiting from the endoplasmic reticulum (ER). Jensen et al. (1995) demonstrated that CFTR and presumably other intrinsic membrane proteins are substrates for proteasomal degradation during their maturation within the endoplasmic reticulum. Chang et al. (1999) showed that export-incompetent CFTR proteins display multiple arginine-framed tripeptide sequences. Inactivation of 4 of these motifs by replacement of arginine residues at positions R29, R516, R555, and R766 with lysine residues simultaneously caused mutant delF508 CFTR protein to escape ER quality control and function at the cell surface. Chang et al. (1999) suggested that interference with recognition of these signals may be helpful in the management of CF.
Younger et al. (2006) identified an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1 (RNF5; 602677), the E2 UBC6E (UBE2J1), and derlin-1 (DERL1; 608813) that cooperated with the cytosolic HSC70 (HSPA8; 600816)/CHIP (STUB1; 607207) E3 complex to triage CFTR and delFl508. Derlin-1 retained CFTR in the ER membrane and interacted with RMA1 and UBC6E to promote proteasomal degradation of CFTR. RMA1 could recognize folding defects in delF508 coincident with translation, whereas CHIP appeared to act posttranslationally. A folding defect in delF508 detected by RMA1 involved the inability of the second membrane-spanning domain of CFTR to productively interact with N-terminal domains. Younger et al. (2006) concluded that the RMA1 and CHIP E3 ubiquitin ligases act sequentially in ER membrane and cytosol to monitor the folding status of CFTR and delF508.
Randak et al. (1997) expressed NBF2 of CFTR as a soluble protein fused to maltose-binding protein in E. coli and found that it catalyzed hydrolysis of ATP to form ADP and Pi. The ADP product inhibited ATPase activity. NBF2 also hydrolyzed GTP to GDP and Pi. In the presence of AMP, however, the ATPase reaction was superseded by adenylate kinase activity, resulting in formation of 2 ADP molecules from ATP and AMP. Randak et al. (1997) identified a typical adenylate kinase-like AMP-binding site in NBF2.
To determine the structural basis for the ATPase activity of CFTR, Ramjeesingh et al. (1999) studied the effect of mutations in the Walker A consensus motifs on ATP hydrolysis by the purified, intact protein. Mutation of the lysine residue in the Walker A motif of either NBF inhibited the ATPase activity of purified, intact CFTR protein by greater than 50%, suggesting that the 2 NBFs function cooperatively in catalysis. Surprisingly, the rate of channel gating was significantly inhibited only when the mutation was in the second NBF, suggesting that ATPase activity may not be tightly coupled to channel gating.
Randak and Welsh (2003) demonstrated that full-length CFTR and the isolated nucleotide-binding domain-2 (NBD2) had ATPase and adenylate kinase activities following expression in HeLa cells. The adenylate kinase inhibitor Ap5A inhibited CFTR Cl- currents, and it inhibited channel activity by binding an ATP site and an AMP site. Adding AMP switched enzymatic activity of the NBD2 polypeptide from ATPase to adenylate kinase. ATP and AMP appeared to induce dimerization between NBD1 and NBD2, causing the channel to open. Randak and Welsh (2003) hypothesized that at physiologic AMP concentrations, the predominant reaction regulating channel activity is likely adenylate kinase.
Jiang and Engelhardt (1998) reviewed the cellular heterogeneity of CFTR expression and function in the lung and the important implications for gene therapy of cystic fibrosis.
Cystic fibrosis is characterized by persistent Pseudomonas aeruginosa colonization of the conducting airways leading to the migration of inflammatory cells, including polymorphonuclear leukocytes (PMNs), into the airways of CF patients. PMNs release a potent chemokinetic and chemoattractant, leukotriene B, during an inflammatory response, resulting in the further migration of inflammatory cells. Cromwell et al. (1981) demonstrated the existence of leukotrienes in the sputum of CF patients. The oxidative metabolites of arachidonic acid and the inflammatory cell-derived proteases have been implicated in the destruction and shedding of the airway epithelia observed in CF. Based on these observations, it has been proposed that antiinflammatory drugs might be useful in CF therapy. The nonsteroidal antiinflammatory drug (NSAID) ibuprofen inhibits 5-lipoxygenase and hence leukotriene formation, suggesting that ibuprofen may be useful in the treatment of CF. Its possible benefit in CF, with no apparent adverse effects, was reported by Konstan et al. (1995). However, other effects of ibuprofen may counteract therapeutic strategies designed to increase CFTR expression and/or function in secretory epithelia. Devor and Schultz (1998) evaluated the acute effects of ibuprofen and salicylic acid on cAMP-mediated Cl- secretion in both colonic and airway epithelia and found that at a pharmacologically relevant concentration the drugs inhibited chloride ion secretion across these epithelia and that this inhibition was due at least in part to the blocking of the CFTR Cl- channels.
Wei et al. (1998) studied CFTR channel activity of mature R-domain mutants with point mutations at sites other than the predicted phosphorylation sites. Whole-cell chloride conduction was increased in Xenopus oocytes injected with H620Q-CFTR mRNA, but decreased in the E822K and E826K mutants compared to wildtype CFTR. Anion permeability and single-channel conductances did not differ from wildtype for any of the mutants. Cell-attached single channel studies in COS cells revealed that both open channel probability and/or the number of functional channels were either higher (H260Q) or lower (E822K and E826K) than in wildtype CFTR. These results suggested that sites other than the phosphorylation sites in the R-domain influence gating.
Chanson et al. (1999) compared gap junctional coupling in a human pancreatic cell line harboring the delF508 mutation in CFTR and in the same cell line in which the defect was corrected by transfection with wildtype CFTR. Exposure to agents that elevate intracellular cAMP or specifically activate protein kinase A evoked chloride ion currents and markedly increased junctional conductance of CFTR-expressing cell pairs, but not in the parental cells. Thus, the expression of functional CFTR restored the cAMP-dependent regulation of junctional conductance as well as the chloride ion channel in CF cells. Consequently, defective regulation of gap junction channels may contribute to the altered functions of tissues affected in CF.
Reddy et al. (1999) demonstrated that in freshly isolated normal sweat ducts, epithelial sodium channel (ENaC; see 600228) activity is dependent on, and increases with, CFTR activity. Reddy et al. (1999) also found that the primary defect in chloride permeability in cystic fibrosis is accompanied secondarily by a sodium conductance in this tissue that cannot be activated. Thus, reduced salt absorption in cystic fibrosis is due not only to poor chloride conductance but also to poor sodium conductance.
Weixel and Bradbury (2000) used in vivo cross-linking and in vitro pull-down assays to show that full-length CFTR binds to the endocytic adaptor complex AP2 (see 601024). Substitution of an alanine residue for tyrosine at position 1424 significantly reduced the ability of AP2 to bind the C terminus of CFTR. However, mutation to a phenylalanine residue, which is normally found in dogfish CFTR at this position, did not perturb AP2 binding. Taken together, these data suggest that the C terminus of CFTR contains a tyrosine-based internalization signal that interacts with the endocytic adaptor complex AP2 to facilitate efficient entry of CFTR into clathrin-coated vesicles.
Wang et al. (2000) identified a hydrophilic CFTR-binding protein, CAP70, which is concentrated on the apical surfaces. CAP70 had previously been identified by Kocher et al. (1998) as PDZK1 (603831). The protein contains 4 PDZ domains, 3 of which are capable of binding to the CFTR C terminus. Linking at least 2 CFTR molecules via cytoplasmic C-terminal binding by either multivalent CAP70 or a bivalent monoclonal antibody potentiates the CFTR chloride channel activity. Thus, the CFTR channel can be switched to a more active conducting state via a modification of intermolecular CFTR-CFTR contact that is enhanced by an accessory protein.
Moyer et al. (2000) reported that the C terminus of CFTR constitutes a PDZ-interacting domain that is required for CFTR polarization to the apical plasma membrane and interaction with the PDZ domain-containing protein EBP50 (604990). PDZ-interacting domains are typically composed of the C-terminal 3 to 5 amino acids, which in CFTR are gln-asp-thr-arg-leu. Point substitution of the leucine at position 0 with alanine abrogated apical polarization of CFTR, interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. Point substitution of the threonine at position -2 with alanine or valine had no effect on the apical polarization of CFTR, but reduced interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. By contrast, individual point substitution of any of the other amino acids in the PDZ domain had no effect on measured parameters. Moyer et al. (2000) concluded that mutations that delete the C terminus of CFTR may cause cystic fibrosis because CFTR is not polarized, complexed with EBP50, or efficiently expressed in the apical membrane of epithelial cells.
CFTR regulates other transporters, including chloride-coupled bicarbonate transport. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. Bicarbonate and pH affect mucin viscosity and bacterial binding. Choi et al. (2001) examined chloride-coupled bicarbonate transport by CFTR mutants that retain substantial or normal chloride channel activity. Choi et al. (2001) demonstrated that mutants reported to be associated with cystic fibrosis with pancreatic insufficiency do not support bicarbonate transport, and those associated with pancreatic sufficiency show reduced bicarbonate transport. Choi et al. (2001) concluded that their findings demonstrate the importance of bicarbonate transport in the function of secretory epithelia and in CF.
Rowntree et al. (2001) showed that removal of a DNase I hypersensitive site (DHS) in intron 1 (185+10 kb) of CFTR abolished the activity of this DHS in transient transfection assays of reporter/enhancer gene constructs. Stable transfections of a human colon carcinoma cell line with CFTR-containing YACs showed that transcription from the DHS element-deleted YAC was reduced by 60% compared to the intact construct. In transgenic mice, deletion of the intron 1 DHS had no effect on expression in the lung, but reduced expression in the intestine by 60%. The authors concluded that the regulatory element associated with the intron 1 DHS is tissue-specific and is required for normal CFTR expression levels in the intestinal epithelium in vivo.
Callen et al. (2000) developed a cAMP-mediated sweat rate test that allows the quantitative discrimination of CFTR function, thereby indicating CF genotype: CF, CF carrier, and non-CF. Callen et al. (2000) remarked that this test may be helpful in the diagnosis of ambiguous cases and in studies of new agents to increase the function of CFTR.
In CFTR, an abbreviated polypyrimidine tract between the branch point A and the 3-prime splice site is associated with increased exon skipping and disease. However, many exons, both in CFTR and in other genes, have short polypyrimidine tracts in their 3-prime splice sites, yet they are not skipped. Hefferon et al. (2002) examined the molecular basis of the skipping of constitutive exons in mRNAs and the skipping of exon 9 in the CFTR gene. They reported observations in human, mouse, and sheep that placed renewed emphasis on deviations at 3-prime splice sites in nucleotides other than the invariant GT, particularly when such changes are found in conjunction with other altered splicing sequences, such as a shortened polypyrimidine tract. Hefferon et al. (2002) suggested that careful inspection of entire 5-prime splice sites may identify constitutive exons that are vulnerable to skipping.
Using a quantitative mRNA assay at 14 time points through ovine gestation, Broackes-Carter et al. (2002) determined that CFTR expression was highest at the start of the second trimester followed by a gradual decline through to term. In contrast, epithelial sodium channel (SCNN1A; 600228) expression increased from the start of the third trimester. The authors proposed a role for CFTR in differentiation of the respiratory epithelium and suggested that its expression levels are not merely reflecting major changes in the sodium/chloride bulk flow close to term.
Eidelman et al. (2002) found that NBF1 of CFTR interacted selectively with phosphatidylserine rather than phosphatidylcholine. In contrast, NBF1 with the delta-F508 mutation lost the ability to discriminate between these phospholipids. In mouse L cells expressing delta-F508 CFTR, replacement of phosphatidylcholine by noncharged analogs led to increased CFTR protein expression, suggesting that aberrant interaction between the delta-F508 NFB1 domain and phospholipid chaperones may contribute to the processing defect of the delta-F508 CFTR mutant.
Plasma membrane expression of delta-F508 CFTR can be rescued in epithelial cells by culturing them at 27 degrees Celsius for 24 hours. By screening 100,000 diverse small molecules, Yang et al. (2003) found that tetrahydrobenzothiophenes could activate cold-induced membrane-associated delta-F508 CFTR, resulting in reversible Cl- conductance in transfected rat thyroid epithelial cells. Single-cell voltage clamp analysis showed characteristic CFTR currents. Activation required low concentrations of a cAMP agonist, mimicking the normal physiologic response.
Reddy and Quinton (2003) reported phosphorylation- and ATP-independent activation of CFTR by cytoplasmic glutamate that exclusively elicits chloride but not bicarbonate conductance in the human sweat duct. They also showed that the anion selectivity of glutamate-activated CFTR is not intrinsically fixed, but can undergo a dynamic shift to conduct bicarbonate by a process involving ATP hydrolysis. Duct cells from patients with the delta-F508 CFTR mutation showed no glutamate/ATP-activated chloride or bicarbonate conductance. In contrast, duct cells from heterozygous patients with R117H (602421.0005)/delta-F508 mutations also lost most of the chloride conductance, yet retained significant bicarbonate conductance. Reddy and Quinton (2003) concluded that not only does glutamate control neuronal ion channels, but it can also regulate anion conductance and selectivity of CFTR in native epithelial cells. They proposed that the loss of this uniquely regulated bicarbonate conductance is most likely responsible for the more severe forms of cystic fibrosis pathology.
Wang et al. (2003) demonstrated that endometrial epithelial cells possess a CFTR-mediated bicarbonate transport mechanism. Coculture of sperm with endometrial cells treated with antisense oligonucleotide against CFTR, or with bicarbonate secretion-defective CF epithelial cells, resulted in lower sperm capacitation and egg-fertilizing ability. These results were considered consistent with a critical role of CFTR in controlling uterine bicarbonate secretion and the fertilizing capacity of sperm, providing a link between defective CFTR and lower female fertility in CF.
Sheep and human CFTR genes show a gradual decline in expression during lung development, from the early midtrimester through to term. Mouchel et al. (2003) identified a novel 5-prime exon of the sheep CFTR gene (ov1a) that occurs in 2 splice forms (ov1aL and ov1aS), which are both mutually exclusive with exon 1. CFTR transcripts, including ov1aL and ov1aS, were present at low levels in many sheep tissues; however, ov1aS showed temporal and spatial regulation during fetal lung development, being most abundant when CFTR expression starts to decline. Alternative 5-prime exons -1a and 1a in the human CFTR gene also showed changes in expression levels through lung development. Structural evaluation of ov1aL and ov1aS revealed the potential to form extremely stable secondary structures which would cause ribosomal subunit detachment. Further, the loss of exon 1 from the CFTR transcript removed motifs that are thought crucial for normal trafficking of the CFTR protein. Mouchel et al. (2003) hypothesized that recruitment of these alternative upstream exons may represent a novel mechanism of developmental regulation of CFTR expression.
Fischer et al. (2004) found that vitamin C induced the opening of CFTR chloride channels by increasing the average open probability in the absence of detectable increased cAMP levels. Exposure of the apical airway surface to physiologic concentrations of vitamin C stimulated transepithelial chloride secretion. When instilled into the nasal epithelium of human subjects, vitamin C activated chloride transport. Fischer et al. (2004) concluded that cellular vitamin C, via its apical vitamin C transporter, is a biologic regulator of CFTR-mediated chloride secretion in epithelia.
Vergani et al. (2005) used single-channel recording methods on intact CFTR molecules to directly follow opening and closing of the channel gates, and related these occurrences to ATP-mediated events in the nucleotide binding domains (NBDs). They found that energetic coupling between 2 CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The 2 monitored side chains are independent of each other in closed channels but become coupled as the channels open. Vergani et al. (2005) concluded that their results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily.
Using proteomics to assess global CFTR protein interactions, Wang et al. (2006) showed that HSP90 (see 140571) cochaperones modulated HSP90-dependent stability of CFTR protein folding in the ER. Small interfering RNA-mediated partial silencing of the HSP90 cochaperone ATPase regulator AHA1 (AHSA1; 608466) in human embryonic kidney and lung cell lines rescued delivery of CFTR delta-F508 to the cell surface. Wang et al. (2006) proposed that failure of CFTR delta-F508 to achieve an energetically favorable fold in response to steady-state dynamics of the chaperone folding environment is responsible for the pathophysiology of CF.
Using proteomic approaches, Thelin et al. (2007) showed that filamin (FLNA; 300017) associates with the extreme CFTR N terminus, and found that the disease-causing S13F mutation disrupts this interaction. Cell studies revealed that FLNA tethers plasma membrane CFTR to the underlying actin network, stabilizing CFTR at the cell surface and regulating the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR is rapidly internalized from the cell surface, where it accumulates prematurely in lysosomes and is ultimately degraded. Thelin et al. (2007) concluded that the CFTR N terminus plays a role in the regulation of the plasma membrane stability and metabolic stability of CFTR, and stated that S13F is the first missense mutation in CFTR found to disrupt a protein-protein interaction.
Coimmunoprecipitation analysis and immunofluorescence microscopy by Cheng et al. (2002) showed that CAL (GOPC; 606845) interacted with the C terminus of CFTR in the Golgi. Functional analysis indicated that the CAL-CFTR interaction resulted in a reduction of the CFTR chloride current by a selective inhibition of cell surface CFTR expression; this could be reversed by competition from NHERF (604990).
Cheng et al. (2010) showed that both syntaxin-6 (STX6; 603944) and CAL were involved in downregulation of CFTR via lysosome-mediated degradation. STX6 bound the N terminus of CFTR, and CAL independently bound the C terminus of CFTR. Overexpression of STX6 reduced cell surface expression of CFTR and caused its instability, but not in the absence of CAL and not in the presence of a lysosome inhibitor. Conversely, overexpression of a dominant-negative STX6 mutant or knockdown of STX6 resulted in CFTR stability. STX6 and CAL had no effect on the stability of delta-F508 CFTR, which is retained in the ER and undergoes ER-associated degradation. Cheng et al. (2010) concluded that STX6 and CAL function in the trans-Golgi network and direct trafficking of CFTR to the lysosome.
By coimmunoprecipitation of transfected COS-7 and CHO-K1 cells, Rode et al. (2012) found that human testis anion transporter-1 (TAT1, or SLC26A8; 608480) interacted with the Cl- and HCO3- conductor CFTR. The 2 proteins colocalized at the equatorial segment of the human sperm head, with partial colocalization at the annulus. Similar colocalization was observed in mouse sperm. Voltage clamp experiments showed that TAT1 enhanced PKA (see 188830)-stimulated currents in CFTR-expressing Xenopus oocytes and stimulated cAMP-dependent CFTR-mediated iodide efflux in transfected CHO-K1 cells. TAT1 alone did not mediate iodide efflux in CHO-K1 cells and did not affect whole-cell conductance in Xenopus oocytes, suggesting that TAT1 is an electroneutral anion exchanger. Rode et al. (2012) concluded that TAT1 and CFTR cooperate in the regulation of Cl-/HCO3- fluxes required for sperm motility and capacitation.
By overexpression and knockdown analyses, Ousingsawat et al. (2011) showed that TMEM16A (610108) formed Ca(2+)-activated Cl- channels (CaCCs) in human airway epithelial cells and that TMEM16A was inhibited by CFTR (602421). However, knockdown analysis in HEK293 cells revealed that CFTR currents were largely independent of other TMEM16 isoforms. CFTR and TMEM16A had an inverse relationship, as CFTR currents were attenuated by additional expression of TMEM16A in HEK293 cells. CFTR and TMEM16A localized to the membrane and appeared to interact physically.
El Khouri et al. (2013) found that the RING-dependent E3 ligase RNF185 (620096) was transcriptionally induced during the unfolded protein response (UPR) and was associated with ER-associated degradation (ERAD). RNF185 targeted CFTR to ERAD to regulate CFTR turnover by inducing ubiquitin-proteasome-dependent degradation of CFTR proteins during translation. Further analysis indicated that RNF5 and RNF185 had redundant function in the control of CFTR stability.
Benedetto et al. (2017) found that Ca(2+)-activated and cAMP-stimulated Cftr-dependent chloride secretion depended on Tmem16a expression, as knockout of Tmem16a eliminated Cftr currents in mouse intestinal epithelial cells and mouse respiratory epithelial cells. Analysis with human airway epithelial cells further established that Cl- currents by CFTR and TMEM16A were functionally linked and interdependent. Mechanistically, TMEM16A enhanced Ca(2+) store release to provide Ca(2+) for activation of CFTR in the presence of cAMP through Ca(2+)-dependent adenylate cyclases. TMEM16A also regulated membrane expression of CFTR. Further analysis revealed that CFTR and TMEM16A interacted, likely with the help of adaptor proteins.
Using single-cell RNA sequencing and in vivo lineage tracing to study the composition and hierarchy of the mouse tracheal epithelium, Montoro et al. (2018) identified a rare cell type, the Foxi1 (601093)-positive pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that they termed 'hillocks'; and disease-relevant subsets of tuft and goblet cells. Montoro et al. (2018) developed 'pulse-seq,' combining single-cell RNA-seq and lineage tracing, to show that tuft, neuroendocrine, and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the CFTR in both mouse and human. Knockout of Foxi1 in mouse ionocytes caused loss of Cftr expression and disrupted airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. Montoro et al. (2018) concluded that by associating cell type-specific expression programs with key disease genes, they had established a new cellular narrative for airway disease.
Plasschaert et al. (2018) performed single-cell profiling of human bronchial epithelial cells and mouse tracheal epithelial cells to obtain a comprehensive census of cell types in the conducting airway and their behavior in homeostasis and regeneration. The analysis revealed cell states that represent known and novel cell populations, delineated their heterogeneity, and identified distinct differentiation trajectories during homeostasis and tissue repair. In addition, Plasschaert et al. (2018) identified a novel, rare cell type that they called the 'pulmonary ionocyte,' which coexpresses FOXI1, multiple subunits of the vacuolar-type H(+)-ATPase (V-ATPase), and CFTR. Using immunofluorescence, modulation of signaling pathways, and electrophysiology, Plasschaert et al. (2018) showed that Notch signaling (see 190198) is necessary and FOXI1 expression is sufficient to drive the production of the pulmonary ionocyte, and that the pulmonary ionocyte is a major source of CFTR activity in the conducting airway epithelium.
Serohijos et al. (2008) presented a 3-dimensional structure of CFTR, constructed by molecular modeling and supported biochemically, in which phe508 mediates a tertiary interaction between the surface of the N-terminal nucleotide-binding domain and cytoplasmic loop-4 in the C-terminal membrane-spanning domain. This crucial cytoplasmic membrane interface is involved in regulation of channel gating and explains the sensitivity of CFTR assembly to disease-associated mutations in cytoplasmic loop-4, as well as in the N-terminal nucleotide-binding domain.
Cryoelectron Microscopy
Liu et al. (2019) reported 2 cryoelectron microscopy structures of human CFTR in complex with potentiators: one with ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These 2 drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggested that in both cases, hydrogen bonds provided by the protein are important for drug recognition.
Kerem et al. (1989) found that approximately 70% of the mutations in CF patients correspond to a specific deletion of 3 basepairs, which results in the loss of a phenylalanine residue at amino acid position 508 of the putative product of the CF gene (F508del; 602421.0001). Haplotype data based on DNA markers closely linked to the putative disease gene locus suggested that the remainder of the CF mutant gene pool consists of multiple, different mutations. A small set of these latter mutant alleles (about 8%) may confer residual pancreatic exocrine function in a subgroup of patients who are pancreatic sufficient. The discovery that the most common CF abnormality gives rise to the loss of a single amino acid residue in a functional domain suggests that the phenotype of CF is not due to complete loss of function of the gene product. The situation may be comparable to that in sickling disorders, in which a specific subset of mutations in the beta-globin gene gives rise to an altered protein with unusual behavior. Complete absence of function of the beta-globin gene gives rise to a different phenotype, namely, beta-0-thalassemia; similarly, homozygous loss of function of the CF gene may lead to a distinctive phenotype.
Trapnell et al. (1991) studied CFTR mRNA transcripts in respiratory tract epithelial cells recovered by fiberoptic bronchoscopy with a cytology brush. They found that the transcripts reflected the normal and the delta-F508 alleles in appropriate proportions. CFTR mRNA transcripts were expressed in nasal, tracheal, and bronchial epithelial cells in about 1 to 2 copies per cell, more than 100-fold greater than in pharyngeal epithelium. Zeitlin et al. (1992) identified a polyclonal antibody that was used to detect the CFTR glycoprotein in biopsied human nasal and bronchial tissues and in the apical membrane fraction of ileal villus tissue. Levels of the protein were modulated pharmacologically.
Zielenski et al. (1991) found a cluster of highly polymorphic dinucleotide repeats in intron 17b of the CFTR gene, 200 bp downstream from the preceding exon. At least 24 alleles, with sizes ranging from 7 to 56 units of a TA repeat, were identified in a panel of 92 unrelated carriers of CF. The common alleles had 7, 30, and 31 dinucleotide units, with frequencies of 0.22, 0.19, and 0.12, respectively, among the non-CF chromosomes. A less polymorphic dinucleotide cluster, a CA repeat, was also detected in a region 167 bp downstream from the TA repeat. This varied from 11 to 17 dinucleotide units and appeared to bear an inverse relationship to that of the TA repeats. These repeats were considered to be useful in genetic linkage studies, in counseling CF families with unknown mutations, and in tracing the origins of various mutant CF alleles. Morral et al. (1991) and Chehab et al. (1991) also described repeats within introns of the CFTR gene. The significance of the inverse correlation between the lengths of the 2 repeat regions was not investigated; length compensation may be involved and may have functional importance.
Chalkley and Harris (1991) made use of 'ectopic' or 'illegitimate' transcription of CF mRNA in leukocytes in the detection of CF mutations. By use of PCR, it was possible to detect such ectopic transcription as in the case of other genes such as those for dystrophin (300377) and factor VIII (300841). Fonknechten et al. (1992) extended these observations, using the PCR reaction for detecting CFTR mutations in the study of lymphocytes and lymphoblasts. Ferrie et al. (1992) applied the amplification refractory mutation system (ARMS) to the detection of mutations in the CFTR gene.
Cutting et al. (1990) sought mutations in the 2 NBFs of CFTR by nucleotide sequencing of exons 9, 10, 11, and 12 (encoding the first NBF) and exons 20, 21, and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American black CF patients. They found a cluster of 4 mutations in a 30-bp region of exon 11. Three of the mutations caused amino acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins, and ATP-binding membrane-associated transport proteins. The fourth mutation created a premature termination signal.
To explore the molecular mechanisms responsible for defective chloride transport in patients with CF, Yang et al. (1993) studied the processing, localization, and function of wildtype, delF508 (602421.0001) and G551D (602421.0013) CFTR in retrovirus transduced L cells. They concluded that the molecular pathology of G551D is explained by an abnormality in channel activity, while the defect in delF508 is a combination of mislocalization and instability of the protein in addition to partial defects in channel function. Some of their observations suggested the possibility of pharmacologic therapies for CF based on activating latent CFTR.
Not only is there heterogeneity in the mutations causing cystic fibrosis, but the pathogenetic mechanisms also vary. Deletion of phenylalanine-508 appears to cause disease by abrogating normal biosynthetic processing and thereby resulting in retention and degradation of the mutant protein within the endoplasmic reticulum. Other mutations, such as the relatively common gly551-to-asp mutation, appear to be normally processed and, therefore, must cause disease through some other mechanism. Because both delta-F508 and G551D occur within a predicted nucleotide-binding domain (NBD) of CFTR, Logan et al. (1994) tested the influence of these mutations on nucleotide binding by the protein. They found that G551D and the corresponding mutation in the CFTR second nucleotide binding domain, gly1349-to-asp (G1349D), led to decreased nucleotide binding by CFTR NBDs, while the delta-F508 mutation did not alter nucleotide binding. These results implicated defective ATP-binding as the pathogenic mechanism of a relatively common mutation leading to CF and suggested that structural integrity of a highly conserved region present in over 30 prokaryotic and eukaryotic nucleotide-binding domains may be critical for normal nucleotide binding.
There is a polymorphic string of thymidines at the end of intron 8 of the CFTR gene; 3 different alleles can be found depending on the number of thymidines (5, 7, or 9) present at this site (Chu et al., 1991). The number of thymidines determines the efficiency by which the intron 8 splice acceptor site is used. The efficiency decreases when a shorter stretch of thymidine residues is found. A higher proportion of CFTR transcripts that lack exon 9 sequences, which encode part of the functionally important first nucleotide-binding domain, will therefore be found when a shorter stretch of thymidine residues is present (Chu et al., 1993). If a CFTR gene with the arg117-to-his (R117H) mutation (602421.0005) harbors a T5 allele, the mutant gene will be responsible for CF. An R117H mutant CFTR gene that harbors a T7 allele can either result in CF or CBAVD (Kiesewetter et al., 1993). Teng et al. (1997) noted that the T5 allele results in the most inefficient use of this splice acceptor site. Most CFTR transcripts from a T5 allele will therefore lack exon 9 sequencing. Such exon 9-deficient CFTR transcripts are known to be translated into CFTR proteins that will not mature, and will therefore not function as chloride channels in the apical membrane of epithelial cells. Among CBAVD patients, the frequency of this T5 allele is 4- to 6-fold higher than in the control population (see 602421.0005). Teng et al. (1997) analyzed CFTR transcripts qualitatively and quantitatively in nasal epithelial and vas deferens cells. Alternative splicing of exon 9, which had been known to occur in nasal epithelial cells, also occurred in vas deferens cells. The extent of this alternative splicing was determined by the allele present at the Tn locus at the end of intron 8 of the CFTR gene. However, the proportion of transcripts lacking exon 9 sequences was increased in vas deferens cells compared with nasal epithelial cells, independent of the Tn genotype. Thus, Teng et al. (1997) postulated that tissue-specific differences in the proportion of CFTR transcripts lacking exon 9 sequences may contribute to the tissue-specific disease phenotype observed in individuals with CBAVD.
Besides the polymorphic Tn locus, more than 120 polymorphisms have been described in the CFTR gene. Cuppens et al. (1998) hypothesized that the combination of particular alleles at several polymorphic loci might result in less functional or even insufficient CFTR protein. Analysis of 3 polymorphic loci with frequent alleles in the general population showed that, in addition to the known effect of the Tn locus, the quantity and quality of CFTR transcripts and/or proteins were affected by 2 other polymorphic loci: M470V (602421.0023) and a dinucleotide repeat polymorphism (TG)m. On a T7 background, the (TG)11 allele gave a 2.8-fold increase in the proportion of CFTR transcripts that lacked exon 9, and (TG)12 gave a 6-fold increase, compared with the (TG)10 allele. T5 CFTR genes derived from patients were found to carry a high number of TG repeats, while T5 CFTR genes derived from healthy CF fathers harbored a low number of TG repeats. Moreover, it was found that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation. Such polyvalent mutant genes could explain why apparently normal CFTR genes cause disease. Moreover, they might be responsible for variation in the phenotypic expression of CFTR mutations. This study suggested that genetic and functional studies of polymorphisms in relation to genetic diseases will become of major interest, in relation both to monogenic disorders and complex traits.
In 9 of 16 cases of disseminated bronchiectasis (56%), Pignatti et al. (1996) found the 5T allele in intron 8 (IVS8-5T) and/or a CFTR gene mutation. The results confirmed, at the molecular genetic level, a clinical connection between CF and one obstructive pulmonary disease, disseminated bronchiectasis of unknown origin. Similarly, Girodon et al. (1997) studied 32 patients with disseminated bronchiectasis and a clinically isolated respiratory syndrome. Analysis of all CFTR gene exons and their flanking regions demonstrated 13 CFTR gene mutations in 16 different alleles. Six of these mutations, which had previously been reported as CF defects, were found in 9 alleles. Four patients were compound heterozygotes; 6 were heterozygous for a mutation. Girodon et al. (1997) concluded that CFTR gene mutations may play a role in bronchiectatic lung disease, possibly in a multifactorial context.
It has been proposed that in heterozygous state mutations of the CFTR gene provide increased resistance to infectious diseases, thereby maintaining mutant CFTR alleles at high levels in selected populations. Pier et al. (1998) investigated whether typhoid fever could be one such disease. This disease is initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation. They found that S. typhi, but not the related murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wildtype CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, delta-F508 (602421.0001). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous delta-F508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than did wildtype Cftr mice; no translocation occurred in delta-F508 Cftr homozygous mice. The Cftr genotype had no effect on the translocation of S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound S. typhi in the submucosa of Cftr wildtype mice than in delta-F508 heterozygous mice. Pier et al. (1998) concluded that diminished levels of CFTR in heterozygotes decreases susceptibility to typhoid fever.
Van de Vosse et al. (2005) tested the hypothesis that CFTR heterozygotes have a selective advantage against typhoid, which may be conferred through reduced attachment of S. typhi to the intestinal mucosa. They genotyped patients and controls in a typhoid endemic area in Indonesia for 2 highly polymorphic markers in CFTR and the most common CF mutation, F508del. Consistent with the apparently very low incidence of CF in Indonesia, the F508del mutation was not present in any patients or controls. However, they found significant association between a common polymorphism in intron 8 (16 or 17 CA repeats) and selective advantage against typhoid.
Sharer et al. (1998) studied 134 consecutive patients with chronic pancreatitis (167800) (alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic disease in 60). DNA was examined for 22 mutations of the CFTR gene that together account for 95% of all mutations in patients with cystic fibrosis in the northwest of England where the study was performed. They also determined the length of the noncoding sequence of thymidines in intron 8, since the shorter the sequence, the lower the proportion of normal CFTR mRNA. None of the patients had a mutation on both copies of the CFTR gene. Eighteen patients (13.4%), including 12 without alcoholism, had a CFTR mutation on 1 chromosome, as compared with a frequency of 5.3% among 600 local unrelated partners of persons with a family history of cystic fibrosis (P less than 0.001). A total of 10.4% of the patients had the 5T allele in intron 8 (14 of 134), which is twice the expected frequency (P = 0.008). Four patients were heterozygous for both a CFTR mutation and the 5T allele. Patients with a CFTR mutation were younger than those with no mutations (P = 0.03). None had the combination of sinopulmonary disease, high sweat electrolyte concentrations, and low nasal potential-difference values that is diagnostic of cystic fibrosis.
Similarly, Cohn et al. (1998) studied 27 patients (mean age at diagnosis, 36 years), 22 of whom were female, who had been referred for an evaluation of idiopathic pancreatitis. DNA was tested for 17 CFTR mutations and for the 5T allele in intron 8. The 5T allele reduces the level of functional CFTR and is associated with an inherited form of infertility in males, CBAVD. Cohn et al. (1998) found that 10 patients with idiopathic chronic pancreatitis (37%) had at least 1 abnormal CFTR allele. Eight CFTR mutations were detected. In 3 patients both alleles were affected. These 3 patients did not have lung disease typical of cystic fibrosis on the basis of sweat testing, spirometry, or base-line nasal potential-difference measurements. Nonetheless, each had abnormal nasal cyclic AMP-mediated chloride transport. The genotypes of the 3 patients were delF508/wildtype (602421.0001), 9T/5T in 2, and delF508/R117H (602421.0005), 9T/7T in 1. These are the 2 most common genotypes in patients with CBAVD. These genotypes do not typically cause lung disease. In contrast, lung disease is present in patients with a genotype of delF508/R117H, 9T/5T.
An abbreviated tract of 5T in intron 8 of the CFTR gene is found in approximately 10% of individuals. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, Groman et al. (2004) determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens (277180), 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P less than 0.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7.7, P less than 0.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.
Lee et al. (2003) haplotyped 117 Korean controls and 75 CF patients having bronchiectasis or chronic pancreatitis using 11 polymorphisms in CFTR. Several haplotypes, especially those with Q1352H (602421.0133), IVS8 T5 (602421.0086), and E217G (602421.0134), were found to have disease associations in a case-control study. The common M470V polymorphism (602421.0023) appeared to affect the intensity of the disease association. The T5-V470 haplotype showed higher disease association than T5-M470, but the Q1352H mutation in a V470 background showed the strongest disease association. Nonsynonymous E217G and Q1352H mutations in the M470 background caused a 60 to 80% reduction in CFTR-dependent chloride currents and bicarbonate transport activities. The M470V polymorphic variant in combination with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. The results revealed that interactions between multiple genetic variants in cis affected the final function of the gene products.
Buratti et al. (2001) showed that nuclear factor TDP43 (605078) binds specifically to the UG repeat sequence of CFTR pre-mRNA and, in this way, promotes skipping of CFTR exon 9. Wang et al. (2004) found that the mouse homolog of human TDP43 also inhibits human CFTR exon 9 splicing in a minigene system. Buratti et al. (2004) described experiments consistent with the model in which the TG repeats in the CFTR intron 8 bind to TDP43, and this protein, in turn, inhibits splicing of exon 9. They suggested that their results provide a mechanistic explanation for the association data of Groman et al. (2004) and also an explanation for the variable phenotypic penetrance of the TG repeats. Individual and tissue-specific variability in the concentration of this inhibitory splicing factor may even determine whether an individual will develop multisystemic (non-classic CF) or monosymptomatic (CBAVD) disease.
Audrezet et al. (2002) analyzed the entire coding sequence and exon/intron junctions of the CFTR gene by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in 39 white French patients with idiopathic chronic pancreatitis. A total of 18 mutant alleles were identified in 14 patients (35.9%), among whom 4 were compound heterozygotes. None of the 4 compound heterozygotes were found to have unrecognized CF-related pulmonary symptoms following reevaluation. However, a sweat test done retrospectively was positive in 2 of them. The 5T allele of the polymorphic string of thymidines at the end of intron 8 of the CFTR gene was present in 7 of the 36 patients tested, an allele frequency (9.7%) nearly 2 times greater than the rate of 5% in the general population (P = 0.09).
The molecular pathogenesis of cystic fibrosis has been investigated by analysis of delF508 CFTR in different heterologous systems, revealing an abrogation of CFTR expression by defective protein maturation. Mutant CFTR was found arrested in an early wildtype intermediate, unable to adopt a protease-resistant mature conformation (Cheng et al., 1990; Gregory et al., 1991; Zhang et al., 1998) that enables exit from the endoplasmic reticulum and processing in the Golgi compartment. Prolonged interaction of immature delF508 CFTR with the chaperones calnexin (CANX; 114217) and Hsp70 (see 140550) in experiments by Pind et al. (1994) and Yang et al. (1993), respectively, indicated that the aberrant protein is recognized by the cell's quality control and that premature degradation by the ubiquitin-proteasome pathway occurs in a pre-Golgi compartment (Jensen et al., 1995; Sato et al., 1998). Reduction of temperature (Denning et al., 1992) and addition of chemical chaperones such as glycerol (Sato et al., 1996) and trimethylamine-N-oxide (Brown et al., 1996) overcame impediments in the folding pathway of delF508 CFTR and allowed proper targeting, thus demonstrating that the mutant protein is still capable of assuming a mature conformation. However, at the cell surface, the chloride channel formed therefrom showed a decreased half-life and reduced open probability and sensitivity to stimulation with cAMP agonists.
Kalin et al. (1999) investigated endogenous CFTR expression in skin biopsies and respiratory and intestinal tissue specimens from delF508 homozygous patients and non-CF persons, using immunohistochemical and immunoblot analyses with a panel of CFTR antibodies. CFTR expression was detected at the luminal surface of reabsorptive sweat ducts and airway submucosal glands, at the apex of ciliated cells in pseudostratified respiratory epithelia and of isolated cells of the villi of duodenum and jejunum, and within intracellular compartments of intestinal goblet cells. In delF508 homozygous patients, expression of the mutant protein proved to be tissue specific. Whereas delF508 CFTR was undetectable in sweat glands, the expression in the respiratory and intestinal tracts could not be distinguished from the wildtype by signal intensity or localization. The tissue-specific variation of delF508 CFTR expression from null to apparently normal amounts indicated that delF508 CFTR maturation can be modulated and suggested that determinants other than CFTR mislocalization should play a role in delF508 CF respiratory and intestinal disease.
Welsh and Smith (1993) provided a classification of the mechanisms by which mutations in CFTR cause cystic fibrosis. The grouping of mutations into 5 classes was based on their functional effect: (I) defective protein production; (II) defective protein processing; (III) defective protein regulation; (IV) defective protein conductance; and (V) reduced amounts of functional CFTR protein. Class I, II, and III mutations have been associated with typical severe multiorgan disease on the basis of clinical studies. In contrast, class IV and V mutations appeared to confer sufficient functional CFTR to result in a mild phenotype.
Haardt et al. (1999) reviewed the various classes of CF-associated mutations and added a tentative additional class VI. They suggested that the mutations can be grouped into 2 major categories. The first group includes those mutants that are unable to accumulate at the cell surface, either because of impaired biosynthesis (class I and class V), or because of defective folding at the endoplasmic reticulum (class II). Mutants that belong to the second category are expressed at the cell surface but fail to translocate chloride ions because of a defect in activation (class IV) or channel conductance (class III). Because the biosynthetic processing and macroscopic chloride channel function of some of the truncated CFTR constructs appear to be normal but the biologic stability of their mature, complex-glycosylated form is dramatically reduced, Haardt et al. (1999) proposed a class VI, which would include stability mutants such as those characterized by their experiments.
To study the consequences that disease-causing mutations have on the regulatory function of CFTR, Mickle et al. (2000) transiently expressed CFTR-bearing mutations associated with CF or its milder phenotype, congenital bilateral absence of the vas deferens (277180), and determined whether mutant CFTR could regulate outwardly rectifying chloride channels (ORCCs). CFTR bearing a CF-associated mutation in the first nucleotide-binding domain, delta-F508del (602421.0001), functioned as a chloride channel but did not regulate ORCCs. However, CFTR that had disease-associated mutations in other domains retained both functions, regardless of the associated phenotype. Thus, a relationship between loss of CFTR regulatory function and disease severity is evident for NBD1, a region of CFTR that appears important for regulation of separate channels.
Bronsveld et al. (2001) determined chloride transport properties of the respiratory and intestinal tracts in delta-F508 twins and sibs. In respiratory tissue, the expression of basal CFTR-mediated chloride conductance, demonstrated by 30% of delta-F508 homozygotes, was identified as a positive predictor of milder CF. In intestinal tissue, 4,4-prime-diisothiocyanatostilbene-2,2-prime-disulfonic acid (DIDS)-insensitive chloride secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive chloride secretion was observed mainly in more severely affected patients. Bronsveld et al. (2001) concluded that in delta-F508 patients, the ability to secrete chloride in the organs that are primarily involved in the course of CF is predictive of the CF phenotype.
Bobadilla et al. (2002) determined the distribution of CFTR mutations in as many regions throughout the world as possible in an effort to understand the evolution of the disease in each region and gain insight for decisions regarding screening programs. Although wide mutational heterogeneity was found throughout the world, characterization of the most common mutations in most populations was possible. A significant positive correlation was found between delta-F508 frequency and the CF incidence of regional populations.
Primary sclerosing cholangitis (PSC; see 109720), a slowly progressive cholestatic liver disease characterized by fibroobliterative inflammation of the biliary tract, leads to cirrhosis and portal hypertension and is a major indication for liver transplantation. Sheth et al. (2003) stated that 75 to 80% of cases were associated with inflammatory bowel disease (IBD; 266600) and that 2.5 to 7.5% of patients with IBD develop PSC (Lee and Kaplan, 1995). Sheth et al. (2003) hypothesized that dysfunction of CFTR may explain why a subset of patients with IBD develop PSC. They prospectively evaluated CFTR genotype and phenotype in 19 patients with PSC compared with 18 patients with IBD and no liver disease, 17 with primary biliary cirrhosis (PBC; 109720), 81 with CF, and 51 healthy controls. They found an increased prevalence of CFTR abnormalities in heterozygous state in PSC as demonstrated by molecular and functional analyses, and concluded that these abnormalities may contribute to the development of PSC in a subset of patients with IBD. Eighty-nine percent of PSC patients carried genotypes containing the 1540G variant (602421.0023) resulting in decreased functional CFTR compared with 57% of disease controls (P = 0.03). Only 1 of 19 PSC patients had neither a CFTR mutation nor the 1540G variant. CFTR chloride channel function assessed by nasal potential difference testing demonstrated a reduced median isoproterenol response in PSC patients compared with disease controls and healthy controls.
Pagani et al. (2003) showed that several nucleotide changes in exon 12 of the CFTR gene induced a variable extent of exon skipping, leading to reduced levels of normal transcripts. This was the case in 2 natural mutations--1 of which was gly576 to ala (G576A; 602421.0061), which had previously been considered a neutral polymorphism--and several site-directed silent substitutions. This phenomenon was due to the interference with a regulatory element, which the authors named composite exonic regulatory element of splicing (CERES). The effect of single-nucleotide substitutions at CERES could not be predicted by either serine-arginine-rich (SR) matrices or enhancer identification. Pagani et al. (2003) suggested that appropriate functional splicing assays should be included in genotype screenings to distinguish between polymorphisms and pathogenic mutations.
By testing 19 synonymous changes in nucleotides 13 to 52 of the human CFTR exon 12, Pagani et al. (2005) found that the probability of inducing exon skipping with a single synonymous substitution was approximately 30%, demonstrating that synonymous substitutions can affect splicing and are not neutral in evolution as they can be constrained by splicing requirements. Pagani et al. (2005) suggested that evolutionary selection of genomic variation takes place at 2 sequential levels: splicing control and protein function optimization.
Aznarez et al. (2003) investigated the consequence of 2 CF disease-causing mutations on the function of a putative exonic splicing enhancer (ESE) in exon 13 of the CFTR gene. Both mutations caused aberrant splicing in a predicted manner, supporting a role for the putative ESE sequence in pre-mRNA splicing. In addition, 3 mutations, including D648V (602421.0097), caused aberrant splicing of exon 13 by improving the polypyrimidine tracts of 2 cryptic 3-prime splice sites. The relative levels of 2 splicing factors, Tra2-alpha (TRA2A; 602718) and SF2/ASF (SFRS1; 600812), altered the effect on splicing of some of the exon 13 disease mutations. The authors suggested that the severity of CF may be modulated by changes in the fidelity of CFTR pre-mRNA splicing.
Audrezet et al. (2004) reported the first systematic screening of the 27 exons of the CFTR gene for large genomic rearrangements, by means of the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Although many disease alleles of CFTR had previously been identified, up to 30% of disease alleles still remained to be identified in some populations, and it had been suggested that gross genomic rearrangements could account for these unidentified alleles. Audrezet et al. (2004) studied a well-characterized cohort of 39 patients with classic CF carrying at least 1 unidentified allele. Using QMPSF, approximately 16% of the previously unidentified CF mutant alleles were identified and characterized, including 5 novel mutations (1 large deletion and 4 insertions/deletions). The breakpoints of these 5 mutations were precisely determined. Although nonhomologous recombination may be invoked to explain all 5 complex lesions, each mutation appeared to have arisen through a different mechanism. One of the insertions/deletions was highly unusual in that it involved the insertion of a short 41-bp sequence with partial homology to a retrotranspositionally-competent LINE-1 element. Audrezet et al. (2004) suggested that the insertion of this ultra-short LINE-1 element (dubbed a 'hyphen element') may constitute a novel type of mutation associated with human genetic disease.
Dinucleotide repeats are ubiquitous features of eukaryotic genomes. The highly variable nature of dinucleotide repeats makes them particularly interesting candidates for modifiers of RNA splicing when they are found near splicing signals. An example of a variable dinucleotide repeat that affects splicing is a TG repeat located in the splice acceptor of exon 9 of the CFTR gene. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens (277180) or nonclassic cystic fibrosis. Using a CFTR minigene system, Hefferon et al. (2004) studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Placement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacement of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing; however, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution with TA repeats of differing length confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Hefferon et al. (2004) concluded that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype.
Wong et al. (2003) described pancreatic-insufficient CF in a child whose father was from Taiwan and mother from Vietnam. The child had 2 different null mutations, glu7 to ter (602421.0131) in exon 1 and a 1-bp insertion, 989A (602421.0132), which caused frameshift and a truncated CFTR protein of 306 amino acids. Wong et al. (2003) commented on the fact that East Asian CF patients did not share mutations with patients of other ethnic backgrounds. Even within East Asians, the CFTR mutation spectrum in Chinese patients is distinct from that of Japanese patients.
Chang et al. (2007) identified mutations in the CFTR gene in 14.1% of total alleles and 24.4% of 78 Chinese/Taiwanese patients with idiopathic chronic pancreatitis (ICP; 167800) compared to 4.8% of total alleles and 9.5% of 200 matched controls. The findings indicated that heterozygous carriers of CFTR mutations have an increased risk of developing ICP. The mutations identified were different from those usually observed in Western countries. The T5 allele with 12 or 13 TG repeats was significantly associated with earlier age at onset in patients with ICP, although the frequency of this allele did not differ between patients and controls.
Sun et al. (2006) analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10. Patients selected for this study were positive for both the 5T variant and the major cystic fibrosis mutation, delta-F508. Almost all delta-F508 mutations occur in a 10TG-9T-470M haplotype. Therefore, it is possible to determine the haplotype of the 5T variant in trans. Of the 74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were 12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which they had clinical information, Sun et al. (2006) reported that 17.6% of females (6 of 34) and 66.7% of males (10 of 15) showed symptoms resembling atypical cystic fibrosis. The haplotype with the highest penetrance in females (42%, or 5 of 12) and more than 80% (5 of 6) in males was 12TG-5T-470V. The authors also evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant; 10 of 12 had the 12TG-5T-470V haplotype. Sun et al. (2006) concluded that overall, the 5T variant has a milder clinical consequence than previously estimated in females. The clinical presentations of the 5T variant are associated with the 5T-12TG-470M haplotype.
Alonso et al. (2007) analyzed 1,954 Spanish cystic fibrosis alleles to define the molecular spectrum of mutations. Commercial panels showed a limited detection power, leading to the identification of only 76% of alleles. More sensitive assays identified 12 mutations with frequencies above 1%, the F508del mutation being the most frequent, present on 51% of alleles. In the Spanish population, 18 mutations were needed to achieve a detection rate of 80%. Fifty-one mutations (42%) were observed once. Alonso et al. (2007) identified a total of 121 disease-causing mutations that accounted for 96% of CF alleles.
Effect of Aminoglycoside Antibiotics
In addition to their antimicrobial activity, aminoglycoside antibiotics can suppress premature termination codons by allowing an amino acid to be incorporated in place of the stop codon, thus permitting translation to continue to the normal end of the transcript. The mechanism translation termination is highly conserved among most organisms and is almost always signaled by an amber (UAG), ochre (UAA), or opal (UGA) termination codon. The nucleotide sequence surrounding the termination codon has an important role in determining the efficiency of translation termination. Aminoglycoside antibiotics can reduce the fidelity of translation, predominantly by inhibiting ribosomal 'proofreading,' a mechanism to exclude poorly matched aminoacyl-tRNA from becoming incorporated into the polypeptide chain. In this way aminoglycosides increase the frequency of erroneous insertions at the nonsense codon and permit translation to continue to the end of the gene, as has been shown in eukaryotic cells (Burke and Mogg, 1985), including human fibroblasts (Buchanan et al., 1987).
Howard et al. (1996) demonstrated that 2 CFTR-associated stop mutations could be suppressed by treating cells with low doses of an aminoglycoside antibiotic. Others demonstrated this effect in cultured cells bearing CFTR nonsense mutations and in connection with stop mutations in muscular dystrophy in mice and in vitro in Hurler syndrome (607014), cystinosis (219800), and other disorders.
In a CF bronchial cell line carrying the CFTR W1282X (602421.0022) mutation, Bedwell et al. (1997) demonstrated that treatment with the aminoglycosides G418 and gentamicin restored CFTR expression, as shown by the reappearance of cAMP-activated chloride currents, the restoration of CFTR protein at the apical plasma membrane, and an increase in the abundance of CFTR mRNA levels from the W1282X allele.
Wilschanski et al. (2003) performed a double-blind placebo-controlled crossover trial of intranasal gentamicin in patients with stop mutations in CFTR, in comparison with patients homozygous for the delta-F508 mutation. Nasal potential difference was measured at baseline and after each treatment. Gentamicin treatment caused a significant reduction in basal potential difference in 19 patients carrying stop mutations and a significant response to chloride-free isoproterenol solution. This effect of gentamicin on nasal potential difference occurred both in patients who were homozygous for stop mutations and in those who were heterozygous, but not in patients who were homozygous for delta-F508. After gentamicin treatment, a significant increase in peripheral and surface staining for CFTR was observed in the nasal epithelial cells of patients carrying stop mutations.
Tata et al. (1991) cloned the mouse homolog of the human CFTR gene.
McCombie et al. (1992) used expressed sequence tags to identify homologs of human genes, including CFTR and the LDL receptor gene (606945), in Caenorhabditis elegans. They suggested that C. elegans, because of the extensive information on the physical and genetic map of the organism, might have unique advantages for the study of the function of normal and mutant genes. The same approach was applied even more extensively by Waterston et al. (1992) who, by study of a cDNA library, identified about 1,200 of the estimated 15,000 genes of C. elegans. More than 30% of the inferred protein sequences had significant similarity to existing sequences in databases.
Zeiher et al. (1995) noted that the F508del (602421.0001) mutation disrupts the biosynthetic processing of CFTR so that the protein is retained in the endoplasmic reticulum and is then degraded. As a result, affected epithelia lack CFTR in the apical membrane and lack cAMP-stimulated chloride ion permeability. Dorin et al. (1992) and Snouwaert et al. (1992), as well as others, disrupted the mouse CFTR gene to create null mutant mice that lack CFTR or express greatly reduced amounts of wildtype protein. To understand the pathophysiology of the disease and to evaluate new therapies, Zeiher et al. (1995) used a targeting strategy to introduce the F508del mutation into the mouse CFTR gene. Murine CFTR is 78% identical to human CFTR, and it contains a phenylalanine at residue 508 flanked by 28 amino acids identical to those in human CFTR. They could show that affected epithelia from homozygous F508del mice lacked CFTR in the apical membrane and were chloride ion-impermeable. Forty percent of homozygous animals survived into adulthood and displayed several abnormalities found in human disease and in CFTR null mice.
Van Doorninck et al. (1995) generated a mouse model of CF with the phe508del mutation using the 'hit-and-run' mutagenesis procedure. In this model, the intron structure was not disturbed, in contrast to similar models (Zeiher et al., 1995; Colledge et al., 1995). French et al. (1996) demonstrated that in this model of CF the mutant CFTR was not processed efficiently to the fully glycosylated form in vivo. However, the mutant protein was expressed as functional chloride channels in the plasma membrane of cells cultured at reduced temperature. Furthermore, they could show that the electrophysiologic characteristics of the mouse phe508del-CFTR channels were indistinguishable from normal. In homozygous mutant mice they did not observe a significant effect of genetic background on the level of residual chloride channel activity. The data showed that like its human homolog, the mouse mutant CFTR is a temperature-sensitive processing mutant, and therefore an authentic model for study of pathophysiology and therapy.
Dickinson et al. (2002) replicated the G480C mutation (602421.0083) in the murine Cftr gene using the 'hit-and-run' double recombination procedure. The G480C cystic fibrosis mouse model expressed the G480C mutant transcript at a level comparable to that of wildtype Cftr. The homozygous mutant mice were fertile and had normal survival, weight, tooth color, and no evidence of cecal blockage, despite mild goblet cell hypertrophy in the intestine. Analysis of the mutant protein revealed that the majority of G480C CFTR was abnormally processed and no G480C CFTR-specific immunostaining in the apical membranes of intestinal cells was detected. The bioelectric phenotype of these mice revealed organ-specific electrophysiological effects. In contrast to delta-F508 'hit-and-run' homozygotes, the classic defect of forskolin-induced chloride ion transport was not replicated in the cecum, but the response to low chloride in the nose was clearly defective in the G480C mutant animals.
Of importance to any gene-replacement strategy for treatment of CF is the identification of the cell type(s) within the lung milieu that need to be corrected and an indication whether this is sufficient to restore a normal inflammatory response and bacterial clearance. Oceandy et al. (2002) generated G551D CF mice transgenically expressing the human CFTR gene in 2 tissue compartments previously demonstrated to mediate a CFTR-dependent inflammatory response: lung epithelium and alveolar macrophages. Following chronic pulmonary infection with Pseudomonas aeruginosa, CF mice with epithelial-expressed (but not macrophage-specific) CFTR showed an improvement in pathogen clearance and inflammatory markers compared with control CF animals. The authors concluded that there may be a role for CFTR-mediated events in epithelial cells in response of the lung to bacterial pathogens.
Di et al. (2006) found that alveolar macrophages from Cftr -/- mice retained the ability to phagocytose and generate an oxidative burst, but exhibited defective killing of internalized bacteria. Lysosomes from Cftr -/- macrophages failed to acidify, although they retained normal fusogenic capacity with nascent phagosomes. Di et al. (2006) proposed that CFTR contributes to lysosome acidification and that in its absence phagolysosomes acidify poorly, thus providing an environment conducive to bacterial replication.
The delta-F508 CFTR mutation results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin, a major component of the curry spice turmeric, is a nontoxic calcium-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Egan et al. (2004) found that oral administration of curcumin to homozygous delta-F508 Cftr mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of delta-F508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Egan et al. (2004) concluded that curcumin treatment may be able to correct defects associated with the homozygous expression of the delta-F508 CFTR gene, as it allows for dissociation from ER chaperone proteins and transfer to the cell membrane.
Delayed puberty is common among individuals with cystic fibrosis and is usually attributed to chronic disease and/or poor nutrition. However, delayed puberty has been reported as a feature of CF even in the setting of good nutritional and clinical status (Johannesson et al., 1997). This finding, along with evidence that Cftr is expressed in rat brain, human hypothalamus, and a gonadotropin-releasing hormone secreting line, raised the possibility that some of the pubertal delay in cystic fibrosis could stem directly from alterations in Cftr function that affects the hypothalamic-pituitary-gonadal axis. To examine this hypothesis, Jin et al. (2006) studied pubertal timing in a mouse model of CF engineered to produce a truncated Cftr mRNA and referred to as S489X. Homozygous knockout mice, which have chronic inflammation and gastrointestinal disease, grew more slowly and had later onset of puberty than wildtype animals. Jin et al. (2006) anticipated that the knockout heterozygotes, which have no clinical CF phenotype, might display an intermediate timing of puberty. They found, however, that these mice had earlier onset of puberty, as assessed by vaginal opening (VO), than wildtype. These findings were confirmed in a second independent model of CF engineered to generate the delta-F508 mutation in mice. Again the homozygotes displayed later pubertal timing, and the heterozygotes displayed earlier VO than the wildtype animals. These data provided further evidence that Cftr can directly modulate the reproductive endocrine axis and raised the possibility that heterozygote mutation carriers may have a reproductive advantage.
For further information on animal models for CF, see 219700.
To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, Pezzulo et al. (2012) interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, they studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Pezzulo et al. (2012) showed that in newborn wildtype pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. Pezzulo et al. (2012) found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wildtype pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. Pezzulo et al. (2012) concluded that their results directly linked the initial host defense defect to the loss of CFTR, an anion channel that facilitates bicarbonate transport. Without CFTR, airway epithelial bicarbonate secretion is defective; the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. Pezzulo et al. (2012) also concluded that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.
CFTR was one of the genes used by Mashal et al. (1995) to test their method of mutation detection using bacteriophage resolvases, whose function in vivo is to cleave branched DNA and which have the property of recognizing mismatched bases in double-stranded DNA and cutting the DNA at the mismatch. The new method, termed enzyme mismatch cleavage (EMC) by Youil et al. (1995), who independently developed the method, takes advantage of this characteristic of resolvases to detect individuals who are heterozygous at a given site. Radiolabeled DNA is cleaved by the resolvase at the site of mismatch in heteroduplex DNA and digestion is monitored on a gel. Thus, both the presence and the estimated position of an alteration is revealed. One may think of the resolvase as a restriction enzyme that only recognizes mutations.
In individuals with cystic fibrosis (CF; 219700), Kerem et al. (1989) identified deletion of 3 basepairs in exon 10 of the CFTR gene, leading to deletion of phenylalanine at codon 508 (delta-F508). The exon in which the delta-F508 mutation occurs has been corrected to exon 11; see, e.g., Sharma et al. (2014).
The European Working Group on CF Genetics (1990) published information on the distribution of the delta-F508 mutation in Europe. The data, illustrated with a useful map, indicated a striking cline across Europe from low values of 30% in the southeast (in Turkey) to high values in the northwest (e.g., 88% in Denmark). The group suggested that the spread of the CF gene might have accompanied the migrations of early farmers starting from the Middle East and slowly progressing toward the northwest of Europe. The diffusion of the gene may have been favored by the selective advantage conferred by the gene. Strong association with the so-called haplotype B was demonstrated. The possibility of 'hitchhiking,' i.e., the influence of neighboring genes was discussed. Rozen et al. (1990) found the delta-F508 mutation in 71% of CF chromosomes from urban Quebec province French Canadian families, 55% of those from Saguenay-Lac-Saint-Jean region families and in 70% of those from Louisiana Acadian families. De Braekeleer (1991) estimated that the frequency at birth of cystic fibrosis is 1/926 in the Saguenay-Lac-Saint-Jean region, giving a carrier rate of 1/15. For the same region, Daigneault et al. (1991) reported a prevalence of CF at birth of 1/902 liveborns, and a carrier rate of 1/15. Rozen et al. (1992) found that the delta-F508 mutation was present in 58% of Saguenay-Lac-Saint-Jean CF families, with the G-to-T donor splice site mutation after codon 621 being found in 23%, and the A455E mutation (602421.0007) in 8%. The latter 2 mutations were not found in urban Quebec families. This provided further evidence of the role of founder effect. Among 293 patients, Kerem et al. (1990) found that those who were homozygous for the F508 deletion had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency. Pancreatic insufficiency was present in 99% of the homozygous patients, 72% of those heterozygous for the deletion, and only 36% of patients with other mutations. Wauters et al. (1991) studied the frequency of the delta-F508 mutation among Belgian patients with CF. The mutation was present in 80% of CF chromosomes from 36 unrelated families. Ninety-three percent of the CF chromosomes carrying the delta-F508 mutation also carried haplotype B in this population. Gille et al. (1991) described a strategy for efficient heterozygote screening for the delta-F508 mutation. They showed that PCR could detect a heterozygote in a pool of up to 49 unrelated DNA samples. Lerer et al. (1992) reported that the delta-F508 mutation accounts for 33.8% of Jewish CF alleles.
The Basque population is thought to be one of the oldest in Europe, having been established in western Europe during the late Paleolithic Age. Euskera, the Basque language, is thought to be pre-Indo-European, originating from the first settlers of Europe. The variable distribution of the delF508 mutation in Europe, with higher frequencies in northern Europe and lower frequencies in southern Europe, has been attributed to a spread of the mutation by early farmers migrating from the Middle East during the Neolithic period. However, a very high frequency of this mutation was found in the Basque Provinces, where the incidence of CF is approximately 1 in 4,500. In a study of 45 CF families from the Basque Provinces, Casals et al. (1992) found that the frequency of the delF508 mutation was 87% in the chromosomes of individuals of pure Basque extraction and 58% in those of mixed Basque origin. Casals et al. (1992) proposed that the delF508 mutation was present in Europe more than 10,000 years ago, preceding the agricultural migrations which diluted the mutation rather than introducing it. Ballabio et al. (1990) described an allele-specific amplification method for diagnosing the phenylalanine-508 deletion. Among Pueblo and Navajo Native Americans of the U.S. Southwest, Grebe et al. (1992) found no instance of the delF508 mutation in 12 affected individuals. Clinically, 6 of the affected individuals had growth deficiency and 5 (all from the Zuni Pueblo) had a severe CF phenotype. Four of the 6 Zunis with CF were also microcephalic, a finding not previously noted in CF patients. In an analysis of 640 Spanish cystic fibrosis families, Casals et al. (1997) found that 75 mutations accounted for 90.2% of CF chromosomes - an extraordinarily high heterozygosity. The frequency of the delta-F508 mutation was 53.2%. The next most frequent mutation was gly542 to ter (602421.0009) with a frequency of 8.43%.
Using 3 intragenic microsatellites of the CFTR gene located in introns, Russo et al. (1995) evaluated linkage disequilibrium between each marker and various CF mutations on a total of 377 CF and 358 normal chromosomes from Italian subjects. Results were considered consistent with the hypothesis that all del508 chromosomes derived from a single mutational event. The same hypothesis was valid for 3 other mutations which might have originated more recently than del508.
Grebe et al. (1994) performed molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States. Only 46% (59 of 129) carried mutation F508del (frequency in the general population 67.1%).
In 69 Italian patients with CF due to homozygosity for the delF508 mutation, De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients.
In a 62-year-old woman with idiopathic bronchiectasis (BESC1; 211400) and elevated sweat chloride but normal nasal potential difference, who carried a heterozygous F508del CFTR mutation, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The patient had a forced expiratory volume in 1 second (FEV1) that was 89% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene.
Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery (140571). Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology.
Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene, for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30.
Pankow et al. (2015) reported the first comprehensive analysis of the CFTR and delta-F508 CFTR interactome and its dynamics during temperature shift and inhibition of histone deacetylases. By using a novel deep proteomic analysis method, they identified 638 individual high-confidence CFTR interactors and discovered a delta-F508 deletion-specific interactome, which is extensively remodeled upon rescue. Detailed analysis of the interactome remodeling identified key novel interactors, whose loss promote delta-F508i CFTR channel function in primary cystic fibrosis epithelia or which are critical for CFTR biogenesis. The results of Pankow et al. (2015) demonstrated that global remodeling of delta-F508 CFTR interactions is crucial for rescue, and provided comprehensive insight into the molecular disease mechanisms of cystic fibrosis caused by deletion of F508.
Clinical Trials
Wainwright et al. (2015) conducted two phase 3, randomized, double-blind, placebo-controlled studies that were designed to assess the effects of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator. A total of 1,108 patients 12 years of age or older who were homozygous for the Phe508del CFTR mutation were randomly assigned to receive either lumacaftor (600 mg once daily or 400 mg every 12 hours) in combination with ivacaftor (250 mg every 12 hours) or matched placebo for 24 weeks. The primary endpoint was the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1) at week 24. In both studies, there were significant improvements in the primary endpoint. The difference between active and placebo with respect to mean absolute improvement in the percentage FEV1 ranged from 2.6 to 4.0 percentage points (p less than 0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (p less than 0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the treated groups than in the placebo group. In addition, the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the treated groups. The incidence of adverse events was similar in the treated and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor-ivacaftor versus 1.6% among those who received placebo. Wainwright et al. (2015) concluded that the combination of a CFTR corrector and potentiator, designed to address the underlying cause of cystic fibrosis by targeting CFTR, can benefit the 45% of patients who are homozygous for the Phe508del mutation.
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected deletion of 3 bp in the CFTR gene, resulting in deletion of isoleucine at either position 506 or 507 (delta-I507). Nelson et al. (1991) found the same mutation in homozygous state in 2 sibs with severe pancreatic insufficiency. Orozco et al. (1994) commented on the difficulties in recognizing the ile507-to-del mutation in a compound heterozygote with F508del.
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-T change in nucleotide 1609 in exon 10 of the CFTR gene that caused a premature stop position 493 (Q493X).
Using the method for identifying single-strand conformation polymorphisms (SSCPs) developed by Orita et al. (1989), Dean et al. (1990) identified 3 different mutations associated with mild cystic fibrosis (CF; 219700). All 3 mutations replaced charged amino acids with less polar residues and resulted in changes in the putative transmembrane sections of the molecule. The mutated amino acids were found to be ones conserved in both rodents and amphibians and to lie in a region of CFTR that is believed to form a channel in the membrane. In a family identified as BOS-7, a C-to-G transversion in exon 4 replaced an aspartic acid residue with histidine (D110H). (The Orita method for identifying SSCPs involves amplification of 100-400 bp segments of radiolabeled DNA, which are subsequently denatured and electrophoresed on high resolution, nondenaturing acrylamide gels. Under these conditions each strand of the DNA fragment can fold back on itself in a unique conformation. Mutations within a DNA segment will often alter the secondary structure of the molecule and affect its electrophoretic mobility.)
In 2 presumably unrelated families with mild cystic fibrosis (CF; 219700), Dean et al. (1990) found a 482G-A transition in exon 4 of the CFTR gene, resulting in an arg117-to-his (R117H) substitution.
Gervais et al. (1993) reported that the R117H mutation was present in 4 of 23 patients with congenital absence of the vas deferens (CBAVD; 277180). Three patients had compound heterozygosity for R117H and delF508 (602421.0001), whereas a fourth was a compound heterozygote for R117H and 2322delG. None of the 23 patients had pulmonary evidence of cystic fibrosis. Five patients without the delF508 mutation had unilateral renal agenesis in addition to absence of the vas deferens; these patients may represent a different distinct subset. Bienvenu et al. (1993) described for the first time homozygosity for the R117H mutation in a 30-year-old French male with sterility owing to congenital bilateral absence of the vas deferens. The subject had no respiratory or pancreatic involvement and had a normal sweat electrolyte value. His parents were not consanguineous, and there were no other cases of CBAVD or CF in the family.
Kiesewetter et al. (1993) presented evidence that the chromosome background of the R117H mutation has a profound effect on the phenotype produced. Three length variants of CFTR have been observed with varying degrees of exon 9 splicing depending on variation in the length of the polypyrimidine tract in the splice acceptor site in intron 8 (Chu et al. (1991, 1993)). Varied lengths of a thymidine (T)-tract (5, 7, or 9Ts) were noted in front of the splice acceptor site of intron 8. The 5T variant is present in 5% of the CFTR alleles among Caucasian populations producing almost exclusively (95%) exon 9-minus RNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the R117H mutation: R117H (5T) is found in typical CF patients with pancreatic sufficiency; R117H (7T) is associated with CBAVD. The R117H mutation has been reported in CF patients, males with congenital bilateral absence of the vas deferens, and in an asymptomatic woman. Furthermore, population screening discovered a 19-fold higher than expected number of carriers of this CF mutation. The situation was compared to that in Gaucher disease in which the severity of neuronopathic disease associated with a missense mutation appears to be altered by additional missense mutations in the same allele (Latham et al., 1990).
White et al. (2001) reported a healthy 29-year-old female who was found to be an R117H/delF508 heterozygote. The patient had atopic asthma and infertility, but normal height and weight and no pulmonary symptoms of CF. Analysis of the polythymidine tract showed that the R117H mutation was in cis with a 7T tract and the delta-F508 mutation in cis with a 9T tract. The authors concluded that poly-T studies are important in any patient found to have the R117H mutation, and recommended caution in the genetic counseling of such families.
Thauvin-Robinet et al. (2009) reported the results of a national collaborative study in France to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the R117H+F508del genotype. In 184 R117H+F508del individuals of the French population, including 72 newborns, the disease phenotype was predominantly mild; 1 child had classic cystic fibrosis, and 3 adults had severe pulmonary symptoms. In 5,245 healthy adults with no family history of CF, the allelic prevalence of F508del was 1.06%, R117H;T7 0.27%, and R117H;T5 less than 0.01%. The theoretical number of R117H;T7+F508del individuals in the French populations was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classic CF for R117H;T7+F508del was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Thauvin-Robinet et al. (2009) suggested that R117H should be withdrawn from CF mutation panels used for screening programs.
In 3 sibs with cystic fibrosis (CF; 219700) from a family identified as UT 1446, Dean et al. (1990) found a C-to-G transversion at position 1172 in the CFTR gene, resulting in substitution of proline for aspartic acid (R347P). The mutation destroyed a HhaI restriction site and created a NcoI site.
In 2 chromosomes from patients with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-A change at nucleotide 1496 in exon 9 of the CFTR gene that caused substitution of glutamic acid for alanine at position 455 (A455E). The exon in which the A455E mutation occurs has been corrected to exon 10; see, e.g., Vecchio-Pagan et al. (2016).
In a patient with cystic fibrosis, Kerem et al. (1990) identified a splice mutation in the CFTR gene, a G-to-A change of nucleotide -1 in the acceptor site of intron 10. In a French patient with cystic fibrosis, Guillermit et al. (1990) detected the same mutation: a G-to-A change in the last nucleotide at the 3-prime end of intron 10 nucleotide 1717 minus one. The mutation destroyed a splice site.
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) found a G-to-T change at nucleotide 1756 in exon 11 of the CFTR gene that was responsible for a stop mutation in codon 542 (G542X). Cuppens et al. (1990) found the same mutation in a Belgian patient. The G542X mutation accounted for 7.3% of the CF chromosomes in Belgium, being probably the second most frequent mutation. (In a sample of Belgian CF patients, 68.1% of all CF chromosomes carried the delta-F508 mutation.) The clinical manifestations were mild in a homozygote but were severe in a first cousin who was a genetic compound for G542X and gly458-to-val (602421.0028). Lerer et al. (1992) reported that the gly542-to-ter mutation accounts for 13% of Ashkenazi CF mutations.
Castaldo et al. (1997) described severe liver involvement associated with pancreatic insufficiency and moderate pulmonary expression of CF in a girl, homozygous for the G542X mutation, who died at the age of 10 years.
Loirat et al. (1997) suggested that G542X is probably the Phoenician cystic fibrosis mutation. They showed that the frequency of G542X varies among different towns at regions of origin, being lower in northeastern Europeans than in southwestern Europeans. G542X mutation mapping that they defined by multiple regression of G542X frequencies covered 28 countries (53 geographic points) and was based on data from 50 laboratories. More elevated values of G542X frequency corresponded to ancient sites of occupation by occidental Phoenicians.
In a patient with a severe form of cystic fibrosis, Savov et al. (1995) identified compound heterozygosity for the G542X mutation and an allele with a double mutation (S912L and G1244V; 602421.0135).
In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected compound heterozygosity for a G-to-A change at nucleotide 1778 in exon 11 of the CFTR gene, responsible for substitution of asparagine for serine at position 549 (S549N), and a premature termination mutation, also in exon 11 (R553X; 602421.0014).
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a G-to-T change at nucleotide 1778 in exon 11 of the CFTR gene, responsible for substitution of isoleucine for serine at amino acid 549 (S549I).
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a T-to-G change at nucleotide 1779 in exon 11 of the CFTR gene, resulting in substitution of arginine for serine at amino acid 549 (S549R). Sangiuolo et al. (1991) found the same ser549-to-arg substitution in an Italian patient with severe cystic fibrosis; however, the substitution was caused by an A-to-C change at nucleotide 1777. Thus, the 2 mutations are AGT-to-AGG and AGT-to-CGT. A T-to-C change at nucleotide 1779 would also change serine to arginine.
Romey et al. (1999) reported a novel complex allele in the CFTR gene, combining the S549R mutation due to a T-to-G transversion in exon 11 with the first described sequence change in the minimal CFTR promoter, a T-to-A transversion at position -102 (602421.0122). In a separate publication, Romey et al. (1999) compared the main clinical features of 6 CF patients carrying the complex allele with those of 16 CF patients homozygous for the S549R mutation alone. Age at diagnosis was higher, and current age was significantly higher (P = 0.0032), in the group with the complex allele, compared with the S549R/S549R group. Although the proportion of patients with lung colonization was similar in the 2 groups, the age at onset was significantly higher in the group with the complex allele (P = 0.0022). Patients with the complex allele also had significantly lower sweat test chloride values (P = 0.0028) and better overall clinical scores (P = 0.004). None of the 22 patients involved in this study had meconium ileus. All 16 patients homozygous for S549R, however, were pancreatic insufficient, as compared with 50% of patients carrying the complex allele (P = 0.013). Moreover, the single patient homozygous for the complex allele presented with mild disease at 34 years of age. These observations strongly suggested that the sequence change in the CFTR minimal promoter attenuates the severe clinical phenotype associated with the S549R mutation.
Romey et al. (2000) postulated that the -102T-A sequence change may attenuate the effects of the severe S549R mutation through regulation of CFTR expression. Analysis of transiently transfected cell lines with wildtype and -102A variant human CFTR-directed luciferase reporter genes demonstrated that constructs containing the -102A variant, which creates a Yin Yang 1 (YY1) core element, increases CFTR expression significantly. Electrophoretic mobility shift assays indicated that the -102 site is located within a region of multiple DNA-protein interactions and that the -102A allele recruits specifically an additional nuclear protein related to YY1.
In 7 patients, including 2 sibs, with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a G-to-A change at nucleotide 1784 in exon 11 of the CFTR gene that was responsible for substitution of aspartic acid for glycine at amino acid 551 (G551D). In 6 of these patients the delta-F508 mutation (602421.0001) was present on the other allele; 3 of these patients, aged 11 to 13 years, had mild lung disease with normal pulmonary function test results. In the seventh patient, with mild lung disease, the mutation on the other allele was unknown.
Curtis et al. (1991) described this mutation in 2 sibs in homozygous state and in an unrelated adult who was a compound heterozygote for G551D and delta-I507 (602421.0002). All 3 showed clinically mild disease. The G551D mutation creates an MboI recognition site at codon 551 in the CFTR gene. Burger et al. (1991) suggested that heterozygosity for the G551D mutation is a causative factor in recurrent polyposis nasi (nasal polyps). Hamosh et al. (1992) stated that the gly551-to-asp mutation, which is within the first nucleotide-binding fold of the CFTR, is the third most common CF mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta-F508, Hamosh et al. (1992) studied 79 compound heterozygotes for the 2 mutations in comparison with age- and sex-matched delta-F508 homozygotes from 9 CF centers in Europe and North America. There was less meconium ileus among the compound heterozygotes but otherwise no statistically significant difference was found between the 2 groups. Clinical outcome (after survival of meconium ileus) was indistinguishable.
Delaney et al. (1996) showed that mice carrying the human G551D mutation in the Cftr gene show cystic fibrosis pathology but have a reduced risk of fatal intestinal blockage compared with 'null' mutants, in keeping with the reduced incidence of meconium ileus in G551D patients. The G551D mutant mice showed greatly reduced CFTR-related chloride transport, displaying activity (equivalent to approximately 4% of wildtype Cftr) intermediate between that of 'null' mice and Cftr insertional mutants with residual activity. The authors stated that long-term survival of these animals should provide an excellent model for the study of cystic fibrosis.
The G551D allele is associated characteristically with populations of Celtic descent and is seen at its highest prevalence in regions such as Ireland and Brittany. It is seen in diminishing frequencies as one moves to the southern and eastern portions of Europe. An initially puzzling phenomenon was the relatively high incidence of this mutation in the Czech Republic (3.8%). As pointed out by Bobadilla et al. (2002), however, population movements of the past provide an explanation.
Accurso et al. (2010) reported the results of a 2-phase clinical trial using VX-770, a CFTR potentiator, in 39 adults with cystic fibrosis and at least 1 G551D allele. Subjects received 150 mg of VX-770 every 12 hours for 28 days in phase 2 of the study. All showed a change in the nasal potential difference from baseline of -3.5 mV (range, -8.3 to 0.5; P = 0.02 for the within-subject comparison; P = 0.13 vs placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P = 0.008 within-subject, P = 0.02 vs placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 within-subject, P = 0.56 vs placebo). The VX-770 was well tolerated. None of the subjects withdrew from the study. All severe adverse events resolved without the discontinuation of VX-770.
Ramsey et al. (2011) conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770) in subjects 12 years of age or older with cystic fibrosis and at least 1 G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of the drug every 12 hours (84 subjects, of whom 83 received at least 1 dose) or placebo (83, of whom 78 received at least 1 dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of forced expiratory volume in 1 second (FEV1). The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (p less than 0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have pulmonary exacerbation than were patients receiving placebo, through week 48 (p less than 0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory symptoms domain of the Cystic Fibrosis Questionnaire revised instrument (p less than 0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (p less than 0.001). The change from baseline through week 48 in the concentration of sweat chloride with ivacaftor as compared with placebo was -48.1 mmol per liter (p less than 0.001). The incidence of adverse events was similar with treatment and controls, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs 42%).
On January 31, 2012, the FDA approved Kalydeco, formerly VX-770 (ivacaftor), for use in cystic fibrosis patients with the G551D mutation, as reported by Ledford (2012).
In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a C-to-T change at nucleotide 1789 in exon 11 of the CFTR gene that was responsible for a stop mutation at amino acid 553 (R553X).
Bal et al. (1991) described a patient homozygous for the arg553-to-ter mutation in exon 11. The patient was moderately severely affected. Hamosh et al. (1991) studied a CF patient who was a compound heterozygote for 2 nonsense mutations, R553X and W1316X (602421.0029). The patient had undetectable CFTR mRNA in bronchial and nasal epithelial cells associated with severe pancreatic disease but unexpectedly mild pulmonary disease. The R553X mutation has the fourth highest frequency worldwide, 1.5%, according to the CF Consortium (Hamosh et al., 1991). The patient was a 22-year-old African American female, 1 of 2 patients with mild pulmonary disease reported by Cutting et al. (1990). Cheadle et al. (1992) described a child who despite being homozygous for the R553X mutation had only mild pulmonary disease. They raised the possibility that the lack of CFTR protein in airway cells may be less damaging than the presence of an altered protein, a suggestion advanced by Cutting et al. (1990).
Chen et al. (2005) reported a Taiwanese CF patient who was homozygous for the R553X mutation. He had a severe clinical course, with early onset of chronic diarrhea, failure to thrive, and frequent respiratory infections. The parents, who were not related, were both heterozygous for the mutation. Both of their families were native to Taiwan, having been on the island for at least 3 generations. Chen et al. (2005) noted that cystic fibrosis is rare among Asians and that homozygosity for R553X had only been reported previously in Caucasian patients.
Aznarez et al. (2007) performed transcript analysis of 5 CF patients who were compound heterozygous for the R553X and delta-F508 (602421.0001) mutations. RT-PCR of patient lymphoblastoid cells showed variable levels of an aberrantly spliced CFTR isoform that corresponded to the skipping of exon 11. Use of a splice reporter construct indicated that the R553X substitution creates a putative exonic splicing silencer (ESS) that may result in exon skipping by preventing selection of the proximal 5-prime splice site. Exon 11 skipping did not result from a nonsense-associated altered splicing mechanism. Aznarez et al. (2007) concluded that aminoglycoside treatment would not be effective for CF patients with this mutation owing to its effect of skipping exon 11.
In a patient with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a G-to-A change at nucleotide 1807 in exon 11 of the CFTR gene that caused a substitution of threonine for alanine at amino acid 559 (A559T).
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) found a G-to-C change at nucleotide 1811 in exon 11 of the CFTR gene responsible for substitution of threonine for arginine at amino acid 560 (R560T).
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) found a T-to-A change at nucleotide 1819 in exon 12 of the CFTR gene responsible for substitution of asparagine for tyrosine at amino acid 563 (Y563N).
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected a C-to-A change at nucleotide 1853 in exon 12 of the CFTR gene responsible for substitution of histidine for proline at amino acid 574 (P574H).
In a patient with cystic fibrosis (CF; 219700), White et al. (1990) detected insertion of 2 nucleotides, AT, after nucleotide 2566 (2566insAT) in exon 13 of the CFTR gene, responsible for a frameshift.
In a patient with cystic fibrosis (CF; 219700), Kerem et al. (1990) detected deletion of a C at nucleotide 3659 in exon 19 of the (3659delC) CFTR gene resulting in a frameshift.
In an 11-year-old black boy with cystic fibrosis (CF; 219700), Cutting et al. (1990) detected a C-to-A change at nucleotide 3896 in exon 20 of the CFTR gene responsible for a stop mutation at amino acid 1255 (S1255X). The boy inherited this mutation from his father. The chromosome inherited from his mother carried another nonsense mutation, gly542-to-ter (602421.0009). The patient had serious pancreatic disease but only mild pulmonary involvement.
In a French patient with cystic fibrosis (CF; 219700), Vidaud et al. (1990) identified the substitution of tryptophan-1282 by a termination codon in the CFTR gene. The other chromosome carried the delta-F508 mutation (602421.0001). In another French patient with cystic fibrosis, Vidaud et al. (1990) found precisely the same mutation on one chromosome but the mutation on the other chromosome was unknown. A G-to-A substitution at nucleotide 3978 was responsible for the trp1282-to-ter change.
Hamosh et al. (1991) cited evidence that the W1282X mutation, located in exon 20, is the most common CF mutation in the Ashkenazi Jewish population where it is present on 50% of CF chromosomes. In Israel, Shoshani et al. (1992) found the W1282X mutation in 63 chromosomes from 97 CF families. Sixteen patients homozygous for the W1282X mutation and 22 patients heterozygous for the delta-F508 and W1282X mutations had similarly severe disease, reflected by pancreatic insufficiency, high incidence of meconium ileus (37% and 27%, respectively), early age at diagnosis, poor nutritional status, and variable pulmonary function. Again, the W1282X mutation was the most common form in Ashkenazi Jewish patients in Israel. In the Jewish Ashkenazi patient population, 60% of the CF chromosomes carry the W1282X nonsense mutation. Patients homozygous for this mutation have severe disease with variable pulmonary complications. Studies by Shoshani et al. (1994) demonstrated that CFTR mRNA levels in patients homozygous for the W1282X mutation are not significantly decreased by the mutation. In patients heterozygous for the mutation, the relative levels of mRNA with the W1282X allele and either the delta-F508 or the normal allele were similar in each patient. These results indicated that the severe clinical phenotype of patients carrying the W1282X mutation is not due to a severe deficiency of mRNA. The severity, progression, and variability of the pulmonary disease appear to be affected by other, as yet unknown factors.
Kulczycki et al. (2003) described their oldest patient with cystic fibrosis, a 71-year-old white male who had been diagnosed at the age of 27 years because of recurrent nasal polyposis, elevated sweat sodium and chloride, and a history of CF in his sister. Urologic examination demonstrated congenital bilateral absence of the vas deferens (277180). At the age of 60 years, genetic testing indicated compound heterozygosity for a severe W1282X mutation and a mild ala445-to-glu (602421.0130) mutation in the CFTR gene. (In the article by Kulczycki et al. (2003), the W1282X mutation was erroneously cited as H1282X.)
Kerem et al. (1990) found 'normal' A or G variation at nucleotide 1540 resulting in methionine or valine, respectively, at position 470.
This variant in the CFTR gene was found by Kobayashi et al. (1990) in a compound heterozygote with delta-F508 (602421.0001). Clinical and epithelial physiologic studies yielded normal results, indicating that the I506V mutation is benign.
This mutation was found by Kobayashi et al. (1990) in a compound heterozygote with delta-F508 (602421.0001). Clinical and epithelial physiologic studies yielded normal results, indicating that the F508C mutation is benign.
In a French patient with cystic fibrosis (CF; 219700), Vidaud et al. (1990) found a replacement of tryptophan-846 by a stop codon on one chromosome; the nature of the mutation on the other chromosome was unidentified.
In a French patient with cystic fibrosis (CF; 219700), Vidaud et al. (1990) identified substitution of tyrosine-913 by cysteine. The other chromosome carried the delta-F508 mutation. An A-to-G substitution at position 2870 was responsible for the tyr913-to-cys change.
In a patient with cystic fibrosis (CF; 219700), Cuppens et al. (1990) described compound heterozygosity for the G542X mutation (602421.0009) and a change of glycine-458 to valine (G458V). The patient died at the age of 12 years of respiratory insufficiency and right heart failure.
In a 21-year-old black woman with cystic fibrosis (CF; 219700) with substantial pancreatic disease but only mild pulmonary involvement, Cutting et al. (1990) found an A-to-G substitution at nucleotide 4079 in exon 21, leading to replacement of tryptophan at codon 1316 by a termination signal. The mutation appeared to have been inherited from the father; from the mother the patient had inherited the arg553-to-ter mutation (602421.0014).
In a 37-year-old woman with cystic fibrosis (CF; 219700) who had a high sweat chloride level, pancreatic insufficiency since infancy, and mild lung disease, Iannuzzi et al. (1991) identified insertion of 2 nucleotides, T and C, at position 1154 of the CFTR gene, predicting a shift in the reading frame of the protein and the introduction of a UAA(ochre) termination codon at residue 369. The patient carried delta-F508 (602421.0001) on the other allele. Alper et al. (2003) described the truncated protein as lacking ATP binding domains, the regulatory domain, and the second transmembrane domain and as thought to be nonfunctional.
Screening 80 CFTR patients, Alper et al. (2003) found two 1154insTC mutations, both in Caucasians, accounting for 1.25% of the CF chromosomes. They also reported compound heterozygosity with delF508 (602421.0001) in CF with pancreatic insufficiency and meconium ileus in a Caucasian male.
In 2 sibs with cystic fibrosis (CF; 219700), Iannuzzi et al. (1991) identified deletion of thymine at position 1213, which was predicted to shift the reading frame of the protein and to introduce a UAA(ochre) termination codon at residue 368. The patients had mildly impaired lung function.
On 4 of 52 chromosomes from patients with cystic fibrosis (CF; 219700), including 2 sibs, Osborne et al. (1991) identified a C-to-G change at nucleotide 4041 of the CFTR gene resulting in a change from asparagine to lysine at amino acid position 1303 (N1303K). This mutation was found exclusively in heterozygous state and no correlation could be made between clinical phenotype and the presence of the gene. Pooling laboratories throughout Europe and the United States, Osborne et al. (1992) identified 216 examples of N1303K among nearly 15,000 CF chromosomes tested, a frequency of 1.5%. The frequency was greater in southern than in northern Europe; it was not found in U.K. Asians, American blacks, or Australians. Ten patients were homozygous, whereas 106 of the remainder carried 1 of 12 known CF mutations in the other allele. Osborne et al. (1992) concluded that N1303K is a 'severe' mutation with respect to the pancreas, but could find no correlation between this mutation in either the homozygous or heterozygous state and the severity of lung disease.
In a study of cystic fibrosis (CF; 219700) mutations in south European cases, Gasparini et al. (1991) found a nonsense mutation in exon 19 due to a C-to-T substitution at nucleotide 3616. The normal codon CGA, which codes for arginine at position 1162, was changed to a stop codon UGA (R1162X). It was detected in 2 of 16 non-delta-F508 chromosomes. In 9 patients homozygous for this mutation, Gasparini et al. (1992) found mild lung disease. They had expected that the interruption in the synthesis of the CFTR protein would result in a severe clinical course. The findings of mild to moderate involvement of the lungs (although pancreatic insufficiency was present in all) suggested to them that this form of truncated CFTR protein, still containing the regulatory region, the first ATP binding domain, and both transmembrane domains, could be partially working in lung tissues.
In the course of a study of cystic fibrosis (CF; 219700) mutations in south European cases, Gasparini et al. (1991) found a C-to-T substitution at nucleotide 1132 in exon 7. This point mutation changed an arginine codon to a tryptophan at position 334 of the putative first transmembrane domain of the protein (R334W). The patient was a compound heterozygote for mutations R334X and N1303K (602421.0032).
Antinolo et al. (1997) compared the phenotype of 12 patients with cystic fibrosis caused by the R334W mutation with those of homozygous delF508 patients. Current age and age at diagnosis were significantly higher in the R334W mutation group. They found a lower rate of Pseudomonas aeruginosa colonization in patients carrying the R334W mutation, although the difference was not statistically significant. However, they found a statistically significant higher age of onset of Pseudomonas aeruginosa colonization in the group of patients with the R334W mutation. Pancreatic insufficiency was found in a lower percentage of R334W patients (33%). The body weight expressed as a percentage of ideal weight for height was significantly higher in patients with the R334W mutation.
In both parents of a sibship in which 3 children with cystic fibrosis (CF; 219700) had died within months of birth (2 with pneumonia and 1 with presumed meconium ileus), Ivaschenko et al. (1991) found the same mutation, namely, deletion of 2 nucleotides (TA) at position 1677. As a result of the deletion, the protein reading frame was shifted, introducing a termination codon (TAG) at amino acid position 515 in the resulting transcript. The family was from a small Soviet ethnic group called the Megrals in western Georgia.
In a compound heterozygote with cystic fibrosis (CF; 219700), White et al. (1991) found a de novo mutation which converted codon 851 (CGA;ARG) to a stop codon (TGA). The mother lacked any CFTR mutation and the father was heterozygous for the common delta-F508 mutation.
In 2 sisters with mild cystic fibrosis (CF; 219700), the offspring of second-cousin parents, Strong et al. (1991) found a G-to-A substitution at basepair 1783 resulting in substitution of a serine for a glycine residue at the highly conserved position of amino acid 551. The proposita was a 50-year-old woman with a chronic productive cough. She had frequent pulmonary infections. Her sweat electrolyte concentrations were borderline normal. The patient had 2 normal pregnancies and deliveries and raised these children while working as a truck inspector. The patient had a sister who died of respiratory failure at the age of 48. She had delivered 4 healthy children without difficulty, had no evidence of malabsorption, and was in good health until the age of 23 when she had an episode of hemoptysis. At that time she was reported to have digital clubbing and bronchiectasis on chest roentgenography. Several sweat tests were normal.
In an 11-year-old boy of Iranian extraction with cystic fibrosis (CF; 219700), Chalkley and Harris (1991) found homozygosity for a G-to-A mutation at nucleotide 386 in exon 3 of the CFTR gene, resulting in substitution of glutamic acid for glycine-85. The diagnosis of CF was made when the patient presented with a nasal polyp. He had sweat sodium values of 90 mmol per liter and mild lung disease and was pancreatic sufficient. The G85E mutation was first defined by Zielenski et al. (1991) in a French Canadian patient who was a compound heterozygote.
In an Italian patient with cystic fibrosis (CF; 219700) known to be a genetic compound, Ronchetto et al. (1992) found a C-to-T transition at nucleotide 3604 of the CFTR gene, which changed an arginine residue at position 1158 to a stop codon (R1158X). The patient carried an unknown mutation on the other chromosome and was pancreatic sufficient.
In an Italian patient with cystic fibrosis (CF; 219700) with pancreatic insufficiency but mild pulmonary disease, Ronchetto et al. (1992) found an A-to-G transition located at the 5-prime end of intron 19 of the CFTR gene, which changed the consensus sequence of the donor site from GTGAGA to GTGGGA (3849+4A-G).
As part of a search for additional mutations causing cystic fibrosis (CF; 219700), Dean et al. (1992) used flanking primers for exon 6A to amplify DNA from over 150 CF patients who lacked the delta-F508 mutation on at least 1 chromosome. In 1 individual, a 22-bp deletion, beginning at nucleotide 852 and stopping 2 bp before the end of the exon, was found. The deletion was predicted to alter the reading frame of the protein, causing the introduction of an in-frame termination codon, TGA, at amino acid 253. Dean et al. (1992) stated that were no documented cases of large deletions and only 1 report of a de novo mutation in the CFTR gene.
In a patient with cystic fibrosis (CF; 219700) with pancreatic insufficiency, Zielenski et al. (1991) identified an exon 4 mutation in CFTR that created a new BglI site, a frameshift due to deletion of nucleotide 556, an A.
In a patient with cystic fibrosis (CF; 219700) with relatively mild symptoms, Graham et al. (1992) identified deletion of a single nucleotide, a T, in the T tract from base 557 to 561 in exon 4 of the CFTR gene. Like the 556A deletion (602421.0042), the mutation created a new BglI site.
In a patient with cystic fibrosis (CF; 219700), Granell et al. (1992) identified an 84-bp deletion in exon 13 of the CFTR gene by DNA amplification and direct sequencing of 500 bp of the 5-prime end of exon 13. The deletion was in the maternal allele, and the patient's paternal allele bore the delta-F508 deletion (602421.0001). The deletion spanned from a 4-A cluster in positions 1949-1952 to another 4-A cluster in positions 2032-2035. The mutation resulted in the loss of 28 amino acid residues in the R domain of the CFTR protein. Since this in-frame mutation, the largest identified to that time, began after nucleotide 1949, it was referred to as 1949del84. Out of 340 Spanish CF patients, Nunes et al. (1992) found 3 patients who were compound heterozygotes for the 1949del84 and delF508 mutations and 1 for 1949del84 and an unknown mutation. The patients had a similar severity of disease to that in delF508 homozygous patients.
In 5 patients with cystic fibrosis (CF; 219700), Nunes et al. (1992) identified a frameshift mutation resulting from insertion of a guanine (G) after nucleotide 2869 in exon 15. One patient was homozygous for the mutation and the other 4 were compound heterozygous. Direct sequencing of the person homozygous for this mutation showed that the mutation resulted in a TGA stop codon at the site of insertion, followed by another stop signal at the beginning of exon 16. The mutation created a new restriction site for the MboI endonuclease. Nunes et al. (1992) demonstrated that the mutation was present in 6 of 191 non-delF508 chromosomes in the Spanish population and in none of 86 Italian non-delF508 chromosomes. All chromosomes carrying the mutation had the same haplotype. A homozygous patient had a moderately severe clinical course. (This mutation is also referred to as 2869insG.)
In a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) used the chemical cleavage mismatch technique to demonstrate a V520F mutation which resulted from a G-to-T transversion.
Using the chemical cleavage mismatch technique for the study of DNA from a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) discovered a nonsense C524X mutation resulting from a C-to-A transversion.
In a patient with cystic fibrosis (CF; 219700), Jones et al. (1992) demonstrated a Q1291H mutation caused by a G-to-C transversion at the last nucleotide of exon 20 using the chemical cleavage mismatch technique. Further study, involving RNA-based PCR, demonstrated that the Q1291H is also a splice mutation. Both correctly and aberrantly spliced mRNAs were produced by the Q1291H allele. The incorrectly spliced product resulted from the use of a nearby cryptic splice site 29 bases into the adjacent intron.
Using DGGE in a systematic study of cystic fibrosis (CF; 219700) mutations in a Celtic population in Brittany, Ferec et al. (1992) identified a C-to-G mutation at nucleotide 1065 of the CFTR gene changing codon 311 from phenylalanine to leucine. The mutation was found in a compound heterozygous child who was classified as pancreatic insufficient; the other allele was gly551-to-asp (602421.0013).
In a systematic study of 365 cystic fibrosis (CF; 219700) chromosomes in the Celtic population in Brittany, Ferec et al. (1992) detected a frameshift mutation in exon 7. The patient, who was severely pancreatic insufficient, was a compound heterozygote for a deletion of 2 nucleotides at position 1221. The other allele had a deletion of T at 1078.
In a systematic study of 365 cystic fibrosis (CF; 219700) chromosomes in the Celtic population in Brittany, Ferec et al. (1992) identified a ser492-to-phe mutation, due to a change at nucleotide 1607 from C to T, in a child classified as pancreatic sufficient.
In a systematic study of 365 cystic fibrosis (CF; 219700) chromosomes in the Celtic population in Brittany, Ferec et al. (1992) identified an arg560-to-lys mutation at the 3-prime end of exon 11, resulting from a G-to-A transition at nucleotide 1811. As well as resulting in an amino acid change in the protein product, the substitution in the last residue of the exon may represent a splice mutation; a similar change in exon 1 of the human beta-globin gene diminishes RNA splicing (Vidaud et al., 1989; see hemoglobin Kairouan; HBB, ARG30THR; 141900.0144). The patient was pancreatic insufficient.
In a child with pancreatic-insufficient cystic fibrosis (CF; 219700) in the Celtic population of Brittany, Ferec et al. (1992) identified a G-to-T change at position 2611 in exon 13 leading to change of glutamic acid-827 to a stop codon.
In a pancreatic-insufficient cystic fibrosis (CF; 219700) patient in the Celtic population of Brittany, Ferec et al. (1992) found an arg1066-to-his mutation resulting from a G-to-A transition at nucleotide 3329. This CpG dinucleotide is a known hotspot for mutations. Ferec et al. (1992) quoted unpublished results indicating that another mutation, C3328 to T leading to arg1066-to-cys, had been discovered (602421.0058). The child with the arg1066-to-his mutation was a compound heterozygote, the other allele having a deletion of T at nucleotide 1078.
In a pancreatic-insufficient child with cystic fibrosis (CF; 219700) in the Celtic population in Brittany, Ferec et al. (1992) found a G-to-A transition at position 3331 resulting in an ala1067-to-thr substitution. The modification replaced a nonpolar residue with a polar residue. The other chromosome carried the delta-F508 mutation (602421.0001).
In a pancreatic-insufficient patient with cystic fibrosis (CF; 219700) in the Celtic population of Brittany, Ferec et al. (1992) identified a G-to-A mutation in the first nucleotide of the splice donor site of intron 20.
In a pancreatic-insufficient patient with cystic fibrosis (CF; 219700) in the Celtic population of Brittany, Ferec et al. (1992) found duplication of 5 nucleotides (CTATG) after nucleotide 3320, creating a frameshift.
Ferec et al. (1992) cited unpublished results of P. Fanen: a C-to-T transition at nucleotide 3328 led to an arg1066-to-cys substitution. This CpG dinucleotide is a hotspot for mutations; see 602421.0054.
See 602421.0050. Claustres et al. (1992) found this mutation in exon 7 in a CF patient with cystic fibrosis (CF; 219700) from southern France. Romey et al. (1993) described an improved procedure that allows the detection of single basepair deletions on nondenaturing polyacrylamide gels and demonstrated its applicability for identifying this mutation.
In a study of 25 unrelated, unselected white azoospermic men with clinically diagnosed congenital bilateral absence of the vas deferens (CBAVD; 277180), aged 24 to 43 years, Anguiano et al. (1992) found 2 in whom there was heterozygosity for the phe508-to-del mutation (602421.0001) with another rare mutation on the other chromosome. In 1 patient, of English/Italian extraction, the second mutation was a G-to-A transition resulting in substitution of asparagine for aspartic acid at amino acid 1270 (D1270N). The patient had a normal chest x-ray and sweat electrolytes well within the normal range. There were no signs of pulmonary or gastrointestinal disease and no signs of overt malabsorption. Thus, the patient had a primarily genital form of cystic fibrosis. Both this mutation and the G576A mutation (602421.0061) occur within the adenosine triphosphate-binding domains of the CFTR protein. These domains are believed to play a role in the regulation of chloride transport. It is possible that the cells of the developing wolffian duct have regulatory pathways functionally associated to CFTR that are different from the lung, pancreas, or sweat duct.
In a man with isolated congenital bilateral absence of the vas deferens (277180), Anguiano et al. (1992) found compound heterozygosity for the phe508-to-del (602421.0001) mutation and another rare mutation: a GGA-to-GCA transversion in codon 576 in exon 12, predicted to cause a substitution of alanine for glycine.
Abeliovich et al. (1992) found that among 94 Ashkenazi Jewish patients with cystic fibrosis (CF; 219700) in Israel, 5 mutations accounted for 97% of mutant CFTR alleles. Four of these were delF508 (602421.0001), G542X (602421.0009), W1282X (602421.0022), and N1303K (602421.0032). The fifth, which accounted for 4% of alleles, was an unusual mutation found by Highsmith (1991). Referred to as 3849+10kbC-T, it was detected by cleavage of a PCR product by HphI. Highsmith et al. (1991) detected the 3849+10kbC-T mutation in a 19-year-old Pakistani woman with mild manifestations of CF and normal sweat chloride values. To explain the milder course of the disease in patients with this mutation, Highsmith et al. (1991) hypothesized that the C-to-T base substitution created an alternative splice site, which resulted in insertion of 84 basepairs into the CFTR coding region. This change may cause synthesis of a protein with normal CFTR function together with a nonfunctional protein. Alternatively, this mutation might lead to production of a protein that is only partly functional and causes milder disease. In Israel, Augarten et al. (1993) investigated 15 patients with CF and this mutation, all Ashkenazi Jews. Their clinical features were compared with those of CF patients with mutations known to be associated with severe disease. Patients with the 3849+10kbC-T mutation were older, had been diagnosed as having CF at a more advanced age, and were in a better nutritional state. Sweat chloride values were normal in 5 of the 15 patients; 4 of these patients and 6 others had normal pancreatic function. However, age-adjusted pulmonary function did not differ between these patients and those with mutations known to cause severe disease. None of the patients with the 3849+10kbC-T mutation had had meconium ileus and none had liver disease or diabetes mellitus.
In 3 pancreatic-insufficient patients with cystic fibrosis (CF; 219700), Cheadle et al. (1992) identified a novel CFTR mutation which, like the trp1282-to-ter mutation (602421.0022), abolishes an MnlII restriction site. The new mutation was found to be a G-to-T transversion at position 3980 resulting in replacement of arginine by methionine at residue 1283 (R1283M).
In 2 patients with cystic fibrosis (CF; 219700), Strong et al. (1992) used chemical mismatch cleavage and subsequent DNA sequencing to identify a splice mutation at the 5-prime end of intron 12 of the CFTR gene. A G-to-A transition at position 1 of the donor-splice site resulted in skipping of exon 12. The mutation was found in compound heterozygous state with the delF508 mutation (602421.0001) in a 39-year-old white male and a 9-year-old female with typical pulmonary and gastrointestinal changes of CF. Both were pancreatic insufficient. The male had a history of liver disease requiring splenorenal shunt for portal hypertension at age 14 years.
Shoshani et al. (1993) found that 88% of identified cystic fibrosis (CF; 219700) chromosomes among CF patients who were Jews from Soviet Georgia had a double mutation in adjacent codons: one alteration was a C-to-A transversion at nucleotide position 1207, changing the glutamine codon to lysine (Q359K); the second alteration was a C-to-A transversion at nucleotide position 1211, changing the threonine codon to lysine (T360K).
In a pancreatic-insufficient cystic fibrosis (CF; 219700) patient, Audrezet et al. (1993) found compound heterozygosity for a delta-F508 mutation and a novel mutation which they designated 876--14 del 12 NT: a large deletion which began at position -14 of exon 6b corresponded to a loss of 12 nucleotides. Because the mutation involved a 4-bp repeat (GATT), the deletion could involve 8 nucleotides depending on the allele in which it occurred.
In a 2-year-old girl with cystic fibrosis (CF; 219700) detected during a systematic neonatal screening who was up to that time symptom free and pancreatic sufficient, Audrezet et al. (1993) found a G-to-T transversion at bp 1172 changing arginine (an amino acid with a basic side chain) to leucine (bearing a nonpolar side chain) at residue 347. Audrezet et al. (1993) pointed out that 2 other mutations involving nucleotide 1172 have been observed, one leading to R347P (602421.0006) and the other to R347H (602421.0078). Both are associated with pancreatic sufficiency.
In the course of screening the normal husband of a heterozygous woman, Audrezet et al. (1993) found a C-to-T transition at nucleotide 1178 predicting substitution of valine for alanine at residue 349. Since both of these amino acids carry a nonpolar side chain, it was not obvious that the variation would lead to a CF allele. However, this nucleotide change was not observed on more than 300 normal chromosomes screened, and alanine at position 349 is conserved in the CFTR gene of human, Xenopus, and cow.
In a screening of 48 patients with cystic fibrosis (CF; 219700) and 12 obligate carriers, Audrezet et al. (1993) observed a C-to-T transition at nucleotide 1733 leading to substitution of glutamic acid for alanine-534 (A534E). The change is a drastic one since it replaces an acidic residue with one that is nonpolar. Observed in heterozygotes, the mutation is probably of functional significance.
In a screening of 48 patients with cystic fibrosis (CF; 219700) and 12 obligate carriers, Audrezet et al. (1993) found an A-to-T transversion at nucleotide 2278 resulting in a stop codon at lysine-716. The mutation was detected in the heterozygous father of a deceased child; no clinical data were available.
In a 2-year-old child with cystic fibrosis (CF; 219700) who carried the delta-F508 mutation (602421.0001) and manifested classic symptoms of CF, namely, pancreatic insufficiency and pulmonary disease, Audrezet et al. (1993) detected on the other chromosome a G-to-A transition in the first nucleotide in the 5-prime splice site of intron 13. Audrezet et al. (1993) referred to this mutation as 2622 +1 G-to-A.
In a patient with classic pancreatic-insufficient CF (CF; 219700), Audrezet et al. (1993) found a C-to-T transition at nucleotide 3844 creating a stop codon (TAG) in place of glutamine (CAG). The other chromosome carried the G542X mutation (602421.0009).
In 3 children with classic cystic fibrosis (CF; 219700), all with pancreatic insufficiency, Audrezet et al. (1993) observed a G-to-A transition at nucleotide -1 of intron 19, involving the splice acceptor site (3850, -1, G-to-A).
In a severely affected, pancreatic-insufficient, 20-year-old patient with cystic fibrosis (CF; 219700), Audrezet et al. (1993) found insertion of a C after nucleotide 3898 resulting in frameshift. The other chromosome carried the R1162X mutation (602421.0033).
In 2 patients with pancreatic-insufficient cystic fibrosis (CF; 219700), Audrezet et al. (1993) found compound heterozygosity for a G-to-A transition at nucleotide 302 in exon 3 converting codon 57 from TGG (trp) to TGA (stop).
In a severely affected, pancreatic-insufficient patient with cystic fibrosis (CF; 219700), Audrezet et al. (1993) found homozygosity for a C-to-T transition at nucleotide 4069 in exon 21 converting gln1313 to a stop codon.
In a Spanish patient with mild cystic fibrosis (CF; 219700), Nunes et al. (1993) found a G-to-A transition at nucleotide 406 resulting in a change of codon 92 in exon 4 from glutamic acid to lysine. The same mutation was found in homozygous state in a Turkish patient with consanguineous parents living in Germany. Both patients were pancreatic sufficient and had normal fat excretion. In both cases physical activity led rapidly to excessive sweating and fatigue; the mother of the Turkish boy reported that after 1 hour of sports the boy's skin and hair became covered with a white salty crust which required 2 or 3 showers to remove.
Audrezet et al. (1993) referred to an R347H mutation causing pancreatic-sufficient cystic fibrosis (CF; 219700). This is 1 of 3 mutations that involve nucleotide 1172, the others being R347P (602421.0006) and R347L (602421.0067).
In a study of 87 non-delF508 chromosomes of Breton origin, Guillermit et al. (1993) found a G91R mutation in 3 pancreatic-sufficient cystic fibrosis patients (CF; 219700). The 3 patients were compound heterozygous for the G91R mutation and delF508 (602421.0001).
In an analysis of 160 cystic fibrosis (CF; 219700) chromosomes, Dorval et al. (1993) detected an F1286S mutation in exon 20 of the CFTR gene using denaturing gel electrophoresis followed by direct sequencing of the PCR products. A T-to-C transition at nucleotide 3989 was responsible for the change from phenylalanine to serine.
By chemical mismatch cleavage in an African American patient with cystic fibrosis (CF; 219700), Smit et al. (1993) found homozygosity for insertion of an adenine after nucleotide 2307 in exon 13. The resulting shift of the reading frame at codon 726 introduced 2 consecutive stop codons at amino acid positions 729 and 730. To examine the mRNA level associated with the 2307insA mutation, RNA from nasal epithelial cells of the patient and a normal subject were reverse transcribed. Subsequent amplification of the cDNA demonstrated that the CFTR message level associated with 2307insA was markedly reduced compared to the normal control, while both the patient and the normal subject showed similar levels of expression.
In each of 4 German patients with cystic fibrosis (CF; 219700), Will et al. (1994) found a G-to-T transversion that affected the first base of exon 4 and created a termination codon glu92-to-ter. Lymphocyte RNA of patients heterozygous for the E92X mutation were found to contain the wildtype sequence and a differentially spliced isoform lacking exon 4. On the other hand, RNA derived from nasal epithelial cells of these patients showed a third fragment of longer length. Sequencing revealed the presence of E92X and an additional 183-bp fragment, inserted between exons 3 and 4. The 183-bp sequence was mapped to intron 3 of the CFTR gene. It was flanked by acceptor and donor splice sites. Will et al. (1994) concluded that the 183-bp fragment in intron 3 is a cryptic CFTR exon that can be activated in epithelial cells by the presence of the E92X mutation. E92X abolishes correctly spliced CFTR mRNA and leads to severe cystic fibrosis.
In a pancreatic-insufficient African American CF (CF; 219700) patient, Smit et al. (1995) found a novel CFTR missense mutation associated with a protein trafficking defect in mammalian cells but normal chloride channel properties in a Xenopus oocyte assay. The mutation resulted in substitution of a cysteine for glycine at residue 480. In mammalian cells, the encoded mutant protein was not fully glycosylated and failed to reach the plasma membrane, suggesting that the G480C protein was subject to defective intracellular processing. However, in Xenopus oocytes, a system in which mutant CFTR proteins are less likely to experience an intracellular processing/trafficking deficit, expression of G480C CFTR was associated with a chloride conductance that exhibited a sensitivity to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) that was similar to that of wildtype CFTR. This appeared to be the first identification of a CFTR mutant in which the sole basis for disease was mislocation of the protein.
The leu206-to-trp (L206W) mutation of the CFTR gene was first identified in 3 cystic fibrosis (CF; 219700) patients from South France (Claustres et al., 1993). Rozen et al. (1995) reported that it is relatively frequent in French Canadians from Quebec. On the basis of findings in 7 French Canadian probands, they suggested that this mutation is likely to be present in patients with atypical forms of CF and may be present in otherwise healthy men and women with infertility. Their group contained 47-year-old and 48-year-old sisters and their 30-year-old brother. The women were thought to have reduced fertility and the man had absence of the vas deferentia. The man and 1 sister had normal pulmonary function and high-resolution CT scan of the chest. The 47-year-old sister had had left upper lobectomy for presumed bronchiectasis at the age of 20 years and had had frequent pulmonary infections but had surprisingly well-preserved lung function.
Clain et al. (2005) noted that the L206W mutation can result in variable disease phenotypes. Individuals bearing this mutation in trans with the severe CF-causing mutation F508del (602421.0001) may have CF or isolated congenital bilateral absence of the vas deferens (277180). Clain et al. (2005) studied the effect of the L206W mutation on CFTR protein production and function and examined the genotype-phenotype correlation of L206W/F508del compound heterozygote patients. They showed that L206W is a processing (class II) mutation, as the CFTR biosynthetic pathway was severely impaired, whereas single-channel measurements indicated ion conductance similar to the wildtype protein. These data raised the larger question of the phenotypic variability of class II mutants, including F508del. Clain et al. (2005) concluded that since multiple potential properties could modify the processing of the CFTR protein during its course to the cell surface, environmental and other genetic factors might contribute to this variability.
Varon et al. (1995) described recurrent nasal polyps as a monosymptomatic form of cystic fibrosis (CF; 219700) in association with a novel in-frame mutation, deletion of 18 bp in exon 4 of the CFTR gene. Since the deletion started with nucleotide 591 of their cDNA clone, the mutation was symbolized 591del18. It was found in male twins of Turkish origin. The twins inherited the 591del18 mutation from their mother. On the paternal allele, they carried the nonsense mutation glu831-to-ter (Verlingue et al., 1994). The patients had been diagnosed as having CF at the age of 10 years due to persistent nasal polyps and elevated sweat electrolytes. Nasal polyps had been surgically removed on 4 occasions. The neonatal period and early infancy were completely uneventful. They were pancreatic sufficient and had no lung disease or other CF-related problems.
Burger et al. (1991) suggested that heterozygosity for the G551D mutation (602421.0013) is a causative factor in recurrent nasal polyps. Presentation with a nasal polyp was the basis of the diagnosis of cystic fibrosis in an 11-year-old boy of Iranian extraction in whom Chalkley and Harris (1991) found homozygosity for a gly85-to-glu mutation (602421.0038).
Zielenski et al. (1995) estimated that CBAVD (277180) is associated with the 5T variant at the 3-prime end of intron 8 of the CFTR gene with a penetrance of 0.60 in males. Chu et al. (1993) noted varied lengths of a thymidine (T)-tract (5, 7, or 9T) in front of the splice-acceptor site of intron 8. The length appeared to correlate with the efficiency of exon 9 splicing, with the 5T variant that is present in 5% of the CFTR alleles among the Caucasian population producing almost exclusively (95%) exon 9-minus mRNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the CF mutation R117H (602421.0005): while R117H (5T) is found in typical CF patients with pancreatic sufficiency, R117H (7T) is associated with CBAVD (Kiesewetter et al., 1993).
Costes et al. (1995) studied the CFTR gene in 45 azoospermic individuals with isolated CBAVD. They detected a CFTR gene defect in 86% of chromosomes from these subjects. In addition to identifying 9 novel CFTR gene mutations, they found that 84% of men with CBAVD who were heterozygous for a CF mutation carried the intron 8 polypyrimidine 5T CFTR allele on 1 chromosome.
De Meeus et al. (1998) found linkage disequilibrium between the 5T allele and the val allele of the met470-to-val polymorphism (602421.0023).
Groman et al. (2004) demonstrated that the number of TG repeats adjacent to 5T influences disease penetrance. They determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. They found that those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats. Thus, determination of TG repeat number will allows for more accurate prediction of benign versus pathogenic 5T alleles.
The TG repeat located at the splice acceptor site of exon 9 of the CFTR gene is an example of a variable dinucleotide repeat that affects splicing. Higher repeat numbers result in reduced exon 9 splicing efficiency and, in some instances, the reduction in full-length transcript is sufficient to cause male infertility due to congenital bilateral absence of the vas deferens or nonclassic cystic fibrosis. Using a CFTR minigene system, Hefferon et al. (2004) studied TG tract variation and observed the same correlation between dinucleotide repeat number and exon 9 splicing efficiency seen in vivo. Replacement of the TG dinucleotide tract in the minigene with random sequence abolished splicing of exon 9. Replacements of the TG tract with sequences that can self-basepair suggested that the formation of an RNA secondary structure was associated with efficient splicing. However, splicing efficiency was inversely correlated with the predicted thermodynamic stability of such structures, demonstrating that intermediate stability was optimal. Finally, substitution of TA repeats of differing lengths confirmed that stability of the RNA secondary structure, not sequence content, correlated with splicing efficiency. Taken together, these data indicated that dinucleotide repeats can form secondary structures that have variable effects on RNA splicing efficiency and clinical phenotype.
In a 66-year-old woman and an unrelated 67-year-old man with idiopathic bronchiectasis (BESC1; 211400), who were heterozygous for the 5T CFTR variant, Fajac et al. (2008) also identified heterozygosity for a missense mutation in the SCNN1B gene (600760.0015). The woman had a borderline elevated sweat chloride, normal nasal potential difference (PD), and FEV1 that was 77% of predicted. The man had normal sweat chloride and nasal PD, and FEV1 that was 80% of predicted. Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene.
In all 8 children of Sardinian descent seen because of hypotonic dehydration associated with hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis, Leoni et al. (1995) found a T338I mutation either in homozygosity or compound heterozygosity with another CF mutation. None had pulmonary or pancreatic involvement. The T338I mutation was not detected in patients with CF who had classic symptoms or in healthy persons of the same descent. Their data suggested that the T338I mutation is associated with a specific mild cystic fibrosis (CF; 219700) phenotype. The patients were seen at ages varying between 2 months and 7 years of age. Three of the patients had failed to thrive. The sweat chloride concentration was high in all patients but 1, who at 3 months of age had borderline values. All the patients had normal steatocrit values for their age, and none of them required pancreatic enzyme supplements.
In 2 of 138 alleles in Jewish patients with cystic fibrosis (CF; 219700), Shoshani et al. (1994) identified a G-to-A transition at nucleotide 3398 of exon 17b of the CFTR gene. This substitution results in a termination codon (TAG) instead of tryptophan at residue 1089. Both mutant chromosomes carry the same extra- and intragenic haplotype, A112.
In a patient of Arab origin with cystic fibrosis (CF; 219700), Shoshani et al. (1994) detected a 4-bp deletion in the CFTR gene, TATT, at position 4010 of the coding sequence using direct sequencing of exon 21. This frameshift mutation is expected to create a termination codon (TAG) 34 amino acids downstream of the mutation. This alteration is likely to be a disease-causing mutation since it is predicted to create a truncated polypeptide that lacks the second ATP binding domain. The patient inherited this deletion from her father. The CFTR chromosome carries the D121 haplotype. Her other CFTR chromosome has the asn1303-to-lys mutation (602421.0032).
This variant, formerly titled CYSTIC FIBROSIS, has been reclassified based on a review of the gnomAD database by Hamosh (2018).
In a study of 224 non-F508del cystic fibrosis (CF; 219700) chromosomes, Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 223, changing arginine to cysteine at position 31, in a French couple with cystic fibrosis and one affected child. Since their apparently unaffected 6-year-old child was found to be homozygous for this mutation, it is probably a polymorphism. The father and the affected child had another substitution changing an isoleucine-556 to valine in exon 11. This mutation can be detected by restriction analysis since it abolishes a HhaI recognition sequence.
Hamosh (2018) found that the I556V variant was present in heterozygous state in 914 of 276,478 alleles and in 28 homozygotes in the gnomAD database, with an allelic frequency of 0.0033 (May 3, 2018).
In a 16-year-old girl with cystic fibrosis (CF; 219700) diagnosed at age 9 months who has remained pancreatic-sufficient, Schaedel et al. (1994) identified an A-to-G substitution at nucleotide 458 in exon 4 of the CFTR gene, converting tyrosine-109 to cysteine (Y109C). Her second mutation was 3659delC (602421.0020) in exon 19. The 3659delC mutation is associated with the pancreatic insufficiency phenotype. The authors concluded that tyr109-to-cys is the mutation conferring pancreatic sufficiency.
In a systematic study of 133 cystic fibrosis (CF; 219700) patients in northern Italy, Gasparini et al. (1993) identified an arg352-to-glu mutation in the CFTR gene.
Ghanem et al. (1994) identified an A-to-G substitution at the fourth nucleotide of the donor splice site of intron 3. It is not known if this mutation is drastic enough to cause aberrant splicing. It could simply be sufficient for a cryptic splice site to be used. This mutation was found on the maternal cystic fibrosis (CF; 219700) chromosome in an African family originating from Cameroon. The CF-affected child, a 9-year-old girl, had no pancreatic insufficiency and no serious lung disease, but suffered from asthma. The sweat chloride was elevated (90 to 110 mmol per liter).
In a systematic study of 133 cystic fibrosis (CF; 219700) individuals in northern Italy, Gasparini et al. (1993) identified a gln524-to-his (Q524H) mutation in the CFTR gene.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in place of glycine-542. In molecular genetic analyses on 129 Hispanic individuals with cystic fibrosis in the southwestern United States, Grebe et al. (1994) found that 5.4% (7 of 129) individuals carried this mutation.
In a cystic fibrosis (CF; 219700) patient with severe pancreatic insufficiency, Gasparini et al. (1993) found a mutation in the CFTR gene that created a stop codon in place of glutamine-552. This mutation was found in 3 of 225 cases.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an asp648-to-val mutation in the CFTR gene.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in place of lysine-710 in the CFTR gene.
In 2 related Portuguese patients with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 2880 in exon 15, resulting in a stop codon at position 890. This mutation was found in a 13-year-old girl and her 15-year-old uncle, who have a classic form of the disease and nasal polyposis. Both patients had F508del on the other CF chromosome, and the uncle had a positive sweat test (140 mmol per liter). The mutation changed the restriction sites MseI(+) and MboII(-).
In a study of 224 non-F508del CF chromosomes, Ghanem et al. (1994) identified a 2867C-T transition in exon 15 of the CFTR gene, resulting in a ser912-to-leu (S912L) substitution, in a CF carrier of French and Spanish extraction. It was difficult to predict whether this substitution would be deleterious.
By in vitro functional expression studies, Clain et al. (2005) demonstrated that the S912L substitution was not disease-causing in isolation, but significantly impaired CFTR function when inherited in cis with another CFTR mutation (see 602421.0135). Clain et al. (2005) identified a healthy father of a CF fetus carrying the S912L mutation. A different CF-producing mutation was identified on the father's other allele. Clain et al. (2005) concluded that the S912L substitution is a neutral variant.
In 2 Spanish patients with cystic fibrosis (CF; 219700), Chillon et al. (1994) identified a 2-bp deletion (TA) in exon 6b of the CFTR gene at position 936 of the coding sequence. This frameshift mutation leads to a premature termination codon 272 nucleotides downstream and a truncated protein. One patient was homozygous and the other compound heterozygous.
In a study of 224 non-F508del cystic fibrosis (CF; 219700) chromosomes, Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 2977 in exon 15, changing histidine to tyrosine at position 949, in a 60-year-old woman with a 10-year history of chronic lung disease. The sweat chloride value was 42 mmol per liter.
In a 10-year-old girl with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a T-to-C substitution at nucleotide 3326 in exon 17b, changing leucine to proline at position 1065 (L1065P). The L1065P mutation was found on the maternal chromosome of the patient, who bore a F508del mutation (602421.0001) on the paternal allele. The leucine at this position is conserved in the mouse CFTR protein. This mutation changes the MnlI(+) restriction site. The patient had gastrointestinal and pulmonary manifestations of cystic fibrosis, as well as high sweat chloride values (66 mmol per liter).
In a 21-year-old woman with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified an A-to-C substitution at nucleotide 3344 in exon 17b, changing glutamine to proline at position 1071 (Q1071P). Since the age of 5 years the patient had suffered from chronic gastrointestinal disorders, pancreatic insufficiency, diarrhea, steatorrhea, and very high sweat chloride values (160 mmol per liter). This missense mutation occurs on an amino acid conserved in mouse CFTR. The patient carried the F508del mutation on the other CF chromosome. The mutation changes the restriction site HaeIII(+).
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified a his1085-to-arg mutation in the CFTR gene.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) found a point mutation creating a stop codon in place of tyrosine-1092 in the CFTR gene.
In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a G-to-A substitution at nucleotide 3743 in exon 19, resulting in a stop codon at position 1204. This mutation was found on the paternal chromosome of a 4-year-old child with pancreatic insufficiency and a sweat chloride level of 120 mmol per liter but no pulmonary infection. The maternal chromosome bears the F508 deletion. The mutation changes the restriction sites MaeI(+).
In a patient with cystic fibrosis (CF; 219700), Romey et al. (1994) identified a 1-bp deletion (G) at nucleotide 2423 in exon 7 of the CFTR gene. This frameshift mutation leads to a premature termination (UAA) 7 codons downstream. The deletion creates an AflIII restriction site and was inherited from the patient's father. The patient, a 7-year-old boy of French and Spanish origin, carries a second mutation 2423delG (602421.0116). Despite the 2 frameshift mutations, this patient does not present a severe form of cystic fibrosis.
In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a C-to-T substitution at nucleotide 3791 in exon 19 of the CFTR gene, changing threonine to isoleucine at position 1220. No other variation in CFTR was found, but the authors could not determine if the variants were found on the same or different alleles. No other family members were available for testing.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an ile1234-to-val mutation in the CFTR gene.
In a patient with cystic fibrosis (CF; 219700), Greil et al. (1994) identified a G-to-A substitution at nucleotide 3878 in exon 20 of the CFTR gene, changing a glycine (GGG) to glutamic acid (GAG) at amino acid 1249.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified a ser1251-to-asn mutation in the CFTR gene.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified a ser1255-to-pro mutation in the CFTR gene.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1993) identified an asp1303-to-his mutation in the CFTR gene.
In a systematic study of 133 patients with cystic fibrosis (CF; 219700) in northern Italy, Gasparini et al. (1992) identified a 2-bp deletion (CA) in exon 10 of the CFTR gene.
In a patient with cystic fibrosis (CF; 219700), Romey et al. (1994) identified a 1-bp (G) deletion at position 2423 of the coding sequence in exon 13 of the CFTR gene. This frameshift mutation leads to a premature termination (UGA) 6 codons downstream. The patient, a 7-year-old boy of French and Spanish origin, carried a second mutation, 1215delG (602421.0108). Despite the 2 frameshift mutations, this patient did not present a severe form of cystic fibrosis. The mutation 2423delG is also associated with sequence variation in intron 17a 3271+18C or T.
In a patient with cystic fibrosis (CF; 219700), Ghanem et al. (1994) identified a 1-bp deletion (A) at position 3293 of the coding sequence in exon 10 of the CFTR gene. This frameshift mutation leads to a premature termination codon 15 nucleotides downstream and a truncated protein. The patient, a 15-year-old F508del heterozygous girl of French origin, has a positive sweat test (80 mmol per liter) and pancreatic insufficiency but no chronic lung infection.
In a 20-year-old cystic fibrosis (CF; 219700) patient of north-central Italian origin with pancreatic insufficiency and severe pulmonary involvement, Sangiuolo et al. (1993) identified a 4-bp insertion (TCAA) at position 3667 of the coding sequence in exon 19 of the CFTR gene. This frameshift mutation leads to a premature termination codon (TGA) at amino acid position 1195 and destroys a HincII restriction enzyme site.
Mickle et al. (1998) identified a 6.8-kb deletion and a nonsense mutation (ser1455 to ter; S1455X) in the CFTR gene of a mother and her youngest daughter with isolated elevated sweat chloride concentrations. Detailed clinical evaluation of both individuals found no evidence of pulmonary or pancreatic disease characteristic of CF. A second child in this family had classic CF and was homozygous for the 6.8-kb deletion, indicating that this mutation caused severe CFTR dysfunction. CFTR mRNA transcripts bearing the S1455X mutation were stable in vivo, implying that this allele encoded a truncated version of CFTR missing the last 26 amino acids. Loss of this region did not affect processing of transiently expressed S1455X-CFTR compared with wildtype CFTR. When expressed in CF airway cells, this mutant generated cAMP-activated whole-cell chloride currents similar to wildtype CFTR. Preservation of chloride channel function of the S1455X-CFTR mutation was consistent with normal lung and pancreatic function in the mother and her daughter. The study indicated that mutations in CFTR can be associated with elevated sweat chloride concentrations in the absence of the CF phenotype, and suggested a previously unrecognized functional role in the sweat gland for the C-terminus of CFTR.
Salvatore et al. (2005) reported 2 asymptomatic sisters with isolated increased sweat chloride concentrations in whom systematic scanning of the whole coding region of the CFTR gene revealed compound heterozygosity for S1455X and delF508 (602421.0001).
Dork et al. (1998) concluded that the 3120+1G-A mutation, which is present in African, Arab, and a few Greek families with cystic fibrosis (CF; 219700), probably was derived from a common ancestor because the haplotypes are very similar or identical.
In a pancreatic-insufficient patient with cystic fibrosis (CF; 219700), Dork et al. (1991) identified a G-to-A transition at nucleotide 1790 of the CFTR gene, resulting in an arg553-to-gln substitution. See also Stern (1997).
For discussion of the T-to-A transversion at position -102 in the minimal CFTR promoter that was found in compound heterozygous state in patients with cystic fibrosis by Romey et al. (1999), see 602421.0012.
Dork et al. (2000) described a large genomic deletion of the CFTR gene that is frequently observed in Central and Eastern Europe. The mutation deletes 21,080 bp spanning from intron 1 to intron 3 of the CFTR gene. Transcript analyses demonstrated that the deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. A simple PCR assay for the allele was devised and used to screen for the mutation in European and European-derived populations. Some 197 cystic fibrosis (CF; 219700) patients, including 7 homozygotes, were identified. Clinical evaluation of the homozygotes and a comparison of compound heterozygotes for delF508 (602421.0001) with pairwise-matched delF508 homozygotes indicated that the 21-kb deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis.
Gomez Lira et al. (2000) postulated that there might be particular CFTR gene mutations involved in pancreatic ductular obstruction, as manifested in idiopathic pancreatitis or in neonatal hypertrypsinemia. Following up on this hypothesis, they performed a complete screening of the CFTR gene in a group of 32 patients with idiopathic pancreatitis (14 of whom carried the 5T variant CF mutation (602421.0086) or had a borderline sweat chloride level, and 18 of whom were without common CF mutations or any other CF characteristic) and in 49 newborns with hypertrypsinemia and normal sweat chloride (32 of whom had a common CF mutation, and 17 of whom did not have a common CF mutation). Rare mutations were found in 9 of 32 patients with idiopathic pancreatitis and in 21 of 49 newborns with hypertrypsinemia. Of these rare mutations, leu997 to phe (L997F) was identified in 4 (12.5%) of 32 patients with idiopathic pancreatitis and in 4 (8%) of 39 newborns with hypertrypsinemia. L997 is a highly conserved residue in transmembrane domain 9.
Since most neonatal screening programs for cystic fibrosis combine the assay of immunoreactive trypsinogen (IRT) with analysis for the most common mutations of the CFTR gene, the identification of heterozygotes among neonates because of increased IRT is considered a drawback. Scotet et al. (2001) assessed the heterozygosity frequency among children with hypertrypsinemia detected during a CF screening program in Brittany (France) 10 years previously. A total of 160,019 babies were screened for CF between 1992 and 1998. Of the 1,964 newborns with increased IRT (1.2%), 60 had CF and 213 were carriers. Heterozygosity frequency was 12.8%, or 3 times greater than in the general population (3.9%). A high proportion of mild mutations or variants was observed in carriers. The allelic frequency of the 5T variant (5.6%) was not increased. The study was consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinemia.
Kabra et al. (2000) identified the L997F mutation in a Pakistani patient with cystic fibrosis (219700), but did not identify the second mutation.
Derichs et al. (2005) reported a child, born of consanguineous Turkish parents, who was homozygous for the L997F substitution. The child showed normal development with no evidence of pancreatic insufficiency or cystic fibrosis. Sweat chloride tests and intestinal chloride secretion were normal. Derichs et al. (2005) concluded that the L997F mutation does not cause cystic fibrosis.
In an Indian child with cystic fibrosis (CF; 219700), Kabra et al. (2000) identified a 1-bp insertion (T) at nucleotide 3622 of the CFTR gene.
In 2 Indian patients with cystic fibrosis (CF; 219700), Kabra et al. (2000) identified a T-to-C change at position -20 from nucleotide 3601 of the CFTR gene.
Wang et al. (2000) found that 7 of 29 Hispanic patients with cystic fibrosis (CF; 219700) were heterozygous for a single-basepair deletion at nucleotide 3876 (3876delA) resulting in a frameshift and termination at residue 1258 (L1258X). This mutation accounted for 10.3% of mutant alleles in this group. The patients with this mutation had a severe phenotype as determined by early age of diagnosis, high sweat chloride, presence of allergic bronchopulmonary aspergillosis, pancreatic insufficiency, liver disease, cor pulmonale, and early death. Wang et al. (2000) noted that this mutation had not been reported in any other ethnic group.
The 394delTT mutation in CFTR causing cystic fibrosis (CF; 219700), referred to as the 'Nordic mutation,' is found at a high frequency in the countries bordering the Baltic Sea and associated waterways (Sweden, Norway, Denmark, Finland, Estonia, Russia, etc.). This mutation is associated almost exclusively with a single chromosomal haplotype, which suggests a single origin, centered in this region (Schwartz et al., 1994).
For discussion of the ala445-to-glu mutation in the CFTR gene that was found in compound heterozygous state in a patient with cystic fibrosis (CF; 219700) by Kulczycki et al. (2003), see 602421.0022.
In a 1.5-year-old Taiwanese boy with cystic fibrosis (CF; 219700), Wong et al. (2003) found compound heterozygosity for 2 novel mutations in the CFTR gene, a G-to-T transversion at nucleotide 151 in exon 1 that resulted in a glu7-to-ter (E7X) substitution in the first transmembrane domain of the protein, and a 1-bp insertion in exon 6b (989_992insA). The insertion caused a frameshift and a truncated CFTR protein of 306 amino acids.
For discussion of the 1-bp insertion (989_992insA) in the CFTR gene that was found in compound heterozygous state in a Taiwanese boy with cystic fibrosis (CF; 219700) by Wong et al. (2003), see 602421.0131.
In a patient with cystic fibrosis (CF; 219700), Lee et al. (2003) identified a G-to-C transversion at nucleotide 4188 in exon 22 of the CFTR gene that resulted in a gln1352-to-his (Q1352H) amino acid change.
In a patient with cystic fibrosis (CF; 219700), Lee et al. (2003) identified a 782A-G transition in exon 6a of the CFTR gene that resulted in a glu217-to-gly (E217G) amino acid substitution.
In a patient with a severe form of cystic fibrosis (CF; 219700), Savov et al. (1995) identified compound heterozygosity for mutations in the CFTR gene. One allele carried a G542X substitution (602421.0009). The other allele carried 2 mutations: S912L (see 602421.0100) and a 3863G-T transversion in exon 20, resulting in a gly1244-to-val (G1244V) substitution in the second nucleotide binding domain.
By in vitro functional expression studies, Clain et al. (2005) demonstrated that the S912L substitution was not disease-causing in isolation, but significantly impaired CFTR function when inherited in cis with the G1244V mutation. Although the G1244V substitution alone resulted in decreased cAMP-dependent chloride conductance (43% of control values), the G1244V/S912L complex allele had an almost 20-fold reduction in chloride conduction (2.4% of control values) compared with the G1244V mutant alone.
Mendes et al. (2003) stated that an ala561-to-glu (A561E) substitution in exon 12 of the CFTR gene is the second most common mutation among Portuguese patients with cystic fibrosis (CF; 219700), accounting for 3% of mutant alleles. Overexpression of the A561E mutant protein in baby hamster kidney cells showed that it was misprocessed and retained in the endoplasmic reticulum, thus belonging to the class II type of CFTR mutation. Low temperature treatment partially rescued a functional A561E-CFTR channel, similar to findings with the common F508del mutation (602421.0001).
Stuhrmann et al. (1997) identified a T-to-A transversion at nucleotide 3302 of the CFTR gene, resulting in met-to-lys substitution at codon 1101 (M1101K) in a single individual with cystic fibrosis (CF; 219700) from the South Tyrol.
In a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified this mutation in heterozygous state in 108 individuals among 1,473 screened and in homozygous state in 6, for a carrier frequency of 0.073 (1 in 13.5). Chong et al. (2012) noted that the South Tyrol was the home of some of the Hutterite founders.
Girardet et al. (2007) reported a male neonate with cystic fibrosis (CF; 219700) who was compound heterozygous for 2 large CFTR rearrangements, one a deletion involving exon 2 inherited from his Sicilian father, and the other a deletion removing exons 16, 17a, and 17b (c.2908+1085_c.3367+260del7201, NM_000492.2) inherited from his South Korean mother. The deletion extended from intron 15 to intron 17b of the gene. Numbering of this mutation uses A of the ATG start codon as the +1 position.
In a Japanese boy diagnosed with CF on the basis of chronic respiratory infection and elevated sweat chloride levels, in whom no mutation had been identified by conventional analysis, Nakakuki et al. (2012) detected the 7.2-kb deletion identified by Girardet et al. (2007) using direct sequencing. A splicing defect was found on the other allele. Nakakuki et al. (2012) predicted that the mutated protein would lack amino acids 970 through 1122, which correspond to transmembrane regions 9, 10, and 11.
Sohn et al. (2019) performed a clinical characterization and genetic analysis of CFTR in 6 Korean patients from 5 families with cystic fibrosis. Six of the 12 alleles (50%) showed the 16-17b multiexon deletion. All 6 patients had a classical cystic fibrosis phenotype and 5 of the 6 presented with meconium ileus. All patients were alive with supportive care at ages ranging from 8 to 19 years. Sohn et al. (2019) suggested molecular investigation for this deletion mutation in Asian populations including Korea and Japan.
Wakabayashi-Nakao et al. (2019) reported identification of a deletion of exons 16-17b in CFTR as the most common Japanese cystic fibrosis variant, with frequency of about 70% among Japanese CF patients definitely diagnosed. The pathogenic mutation results in a deletion of 153 amino acids, from glycine at position 970 (G970) to threonine at 1122 (T1122) in the CFTR protein without a frameshift; the authors referred to the mutation as delta-(G970-T1122). The authors characterized this variant in CFTR carrying this deletion in CHO cells using immunoblots and super-resolution microscopy. The protein is synthesized and core-glycosylated but not complex-glycosylated. Lumacaftor (VX-809) could not rescue the maturation defect of the delta-(G970-T1122) protein. Wakabayashi-Nakao et al. (2019) suggested that this mutation should be characterized as a class II variant.
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