Alternative titles; symbols
SNOMEDCT: 190905008; ICD10CM: E84, E84.9; ICD9CM: 277.0; ORPHA: 586; DO: 1485;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q23.3 | {Pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis} | 219700 | Autosomal recessive | 3 | FCGR2A | 146790 |
| 7q31.2 | Cystic fibrosis | 219700 | Autosomal recessive | 3 | CFTR | 602421 |
| 19q13.2 | {Cystic fibrosis lung disease, modifier of} | 219700 | Autosomal recessive | 3 | TGFB1 | 190180 |
A number sign (#) is used with this entry because cystic fibrosis (CF) is caused by homozygous or compound heterozygous mutation in the cystic fibrosis conductance regulator gene (CFTR; 602421) on chromosome 7q31.
Cystic fibrosis (CF) is classically described as a triad of chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevation of sodium and chloride concentration in sweat. Almost all males with CF are infertile due to congenital bilateral absence of the vas deferens. The disorder is associated with decreased longevity (summary by Cutting, 2002).
For discussion of a phenotype consisting of bronchiectasis with or without elevated sweat chloride caused by mutation in the genes encoding the 3 subunits of the epithelial sodium channel, see BESC1 (211400).
The mildest extreme of CF is represented by patients not diagnosed until middle age (Scully et al., 1977). The phenotypic variability in CF was analyzed by Sing et al. (1982). In an inbred kindred in North Carolina, a mild form of cystic fibrosis was described by Knowles et al. (1989). There was 1 instance of mother-daughter involvement, the mother being related to her husband. One of the presumed homozygotes was a 62-year-old woman. Another was her 52-year-old sister, the mother of the affected proposita. The daughter was an intensive care nurse, the mother of a normal daughter. Manifestations in the family were predominantly pulmonary; pancreatic exocrine insufficiency was not a conspicuous feature, especially in the older patients.
The 2 subgroups defined by the A and C haplotypes of polymorphisms closely linked to the CF locus on chromosome 7, reported by Estivill et al. (1987), have clinical differences in terms of the frequency of meconium ileus, pseudomonas infections, and pancreatic disease (Woo, 1988).
Gasparini et al. (1990) described a RFLP DNA marker closely linked to the CF locus which showed an allelic correlation with severity of the disorder: the genotype 2/2 was associated with severe disease; the genotype 1/2 was overrepresented in patients with very mild clinical manifestations, including pancreatic insufficiency, absence of meconium ileus, and absence of Pseudomonas colonization.
Meconium Ileus
Allan et al. (1981) showed that sibs tend to show recurrence of meconium ileus as a feature of cystic fibrosis. The distal intestinal obstruction syndrome is a 'meconium ileus equivalent' that occurs in adolescents and adults with CF. It is the consequence of the abnormally viscid mucofeculant material in the terminal ileum and right colon, where the fecal stream is normally liquid. Typical features are recurrent episodes of RLQ pain with palpable mass in the right iliac fossa. Symptoms are exacerbated by eating.
Mornet et al. (1988) determined the haplotype associated with cystic fibrosis in 41 families using 4 DNA probes, all of which are tightly linked to the CF gene. In 17 of the families an affected child had meconium ileus, and in the other 24 families there was a child without meconium ileus. A different haplotype was associated with the 2 types of families, suggesting that multiple allelism, i.e., different mutations at the same locus, accounts for CF with or without meconium ileus.
Liver Disease
Gaskin et al. (1988) found that 96% of patients with cystic fibrosis and evidence of liver disease had biliary tract obstruction, usually a stricture of the distal common bile duct. All patients without liver disease had normal intrahepatic and common-duct excretion of tracer.
Bilton et al. (1990) described a case of cystic fibrosis complicated by common bile duct stenosis.
Gabolde et al. (2001) showed that the presence of cirrhosis in patients with cystic fibrosis is significantly associated with either homozygous or compound heterozygous mutations in the MBL2 gene (154545), which encodes mannose-binding lectin (MBL). The authors compared 216 patients homozygous for the delta-F508 mutation (602421.0001) and found that 5.4% of those homozygous or compound heterozygous for wildtype mannose-binding lectin had cirrhosis, while 30.8% of those homozygous or compound heterozygous for mutant alleles had cirrhosis (p = 0.008).
Approximately 3 to 5% of patients with cystic fibrosis develop severe liver disease defined as cirrhosis with portal hypertension. Bartlett et al. (2009) performed a 2-stage case control study enrolling patients with CF and severe liver disease with portal hypertension from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America. In the first stage, 124 patients with CF and severe liver disease, enrolled between January 1999 and December 2004, and 843 control patients without CF-related liver disease (all assessed at greater than 15 years of age) were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the 2 genes that were positive from the first stage were tested in an additional 136 patients with CF-related liver disease, enrolled between January 2005 and February 2007, and in 1,088 with no CF-related liver disease. The combined analysis of the initial and replication studies by logistic regression showed CF-related liver disease to be associated with the SERPINA1 Z allele (107400.0011) (odds ratio = 5.04; 95% confidence interval, 2.88-8.83; p = 1.5 x 10(-8)). Bartlett et al. (2009) concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients carrying the Z allele are at greater risk (odds ratio = approximately 5) of developing severe liver disease with portal hypertension.
Pancreatic Insufficiency
Approximately 15% of CF patients do not have pancreatic insufficiency, i.e., are 'pancreatic sufficient.' Kerem et al. (1989) performed linkage disequilibrium and haplotype association studies of patients in 2 clinical subgroups, one pancreatic insufficient (PI) and the other pancreatic sufficient (PS). Significant differences were found in allelic and haplotype distributions in the 2 groups. The data suggested that most of the CF-PI patients were descendants of a single mutational event at the CF locus, whereas the CF-PS patients resulted from multiple, different mutations. Corey et al. (1989) commented on the intrafamilial concordance for pancreatic insufficiency in CF.
Devoto et al. (1989) studied the allele and haplotype frequencies of 5 polymorphic DNA markers near the CF locus in 355 CF patients from Belgium, the German Democratic Republic, Greece, and Italy who were divided into 2 groups according to whether or not they were taking supplementary pancreatic enzymes. The distributions of alleles and haplotypes revealed by 2 of the probes were always different in patients with or without pancreatic insufficiency in all the populations studied. In the case of 1 haplotype that was present in 73% of all the CF chromosomes in their sample, they found homozygosity in only 28% of patients without pancreatic insufficiency as contrasted with 64% who were homozygous and had pancreatic insufficiency. Like other workers, they concluded that this indicated that pancreatic insufficiency and sufficiency are associated with different mutations at the CF locus.
Ferrari et al. (1990) studied the distribution of haplotypes based on 8 polymorphic DNA markers linked to CF in 163 Italian patients and correlated the findings with clinical presentation. Among 19 pancreatic sufficient patients, 6 (31.6%) showed at least 1 copy of a rare phenotype which was present in only 16 of 138 patients (11.6%) with pancreatic insufficiency. In addition, only 5 pancreatic sufficient patients were homozygous for the common 2,1 haplotype as compared with 88 patients (63.8%) with pancreatic insufficiency. Kristidis et al. (1992) likewise found intrafamilial consistency of the pancreatic phenotype, whether pancreatic sufficient or insufficient. Furthermore, the PS phenotype occurred in patients who had 1 or 2 mild CFTR mutations, such as arg117-to-his (602421.0005), arg334-to-trp (602421.0034), arg347-to-pro (602421.0006), ala455-to-glu (602421.0007), and pro574-to-his (602421.0018), whereas the PI phenotype occurred in patients with 2 severe alleles, such as phe508-to-del (602421.0001), ile507-to-del (602421.0002), gln493-to-ter (602421.0003), gly542-to-ter (602421.0009), arg553-to-ter (602421.0014), and trp1282-to-ter (602421.0022).
Borgo et al. (1993) commented on the phenotypic intrafamilial heterogeneity displayed by an Italian family in which 3 sibs, 2 of whom were dizygotic twins, were compound heterozygotes for the delF508 (602421.0001) and the 1717-1G-A splicing mutation (602421.0008). While close intrafamilial concordance was found for exocrine pancreatic phenotype, the pulmonary phenotype varied widely. They suggested that interaction of the CFTR protein with tissue-specific proteins or the action of modifier loci (which may be operationally identical possibilities) plays a role in intrafamilial variability.
Barreto et al. (1991) concluded that the father of a girl with severe CF also had CF but was mildly affected. The child was homozygous for the delF508 mutation associated with haplotype B; the father was a compound heterozygote for this mutation and a second CF mutation associated with haplotype C. Perhaps it should not be surprising that some patients with cystic fibrosis have no pancreatic lesions (Oppenheimer, 1972).
Sharer et al. (1998) and Cohn et al. (1998) demonstrated that heterozygosity for CFTR mutations can lead to 'idiopathic' chronic pancreatitis, especially when the mutation is associated with the 5T allele of the variable number of thymidines in intron 8 of the CFTR gene.
Pulmonary Disease
Pier et al. (1996) provided an experimental explanation for the susceptibility of CF patients to chronic Pseudomonas aeruginosa lung infections. They found that cultured human airway epithelial cells expressing the delta-F508 allele of the CFTR gene were defective in uptake of P. aeruginosa compared with cells expressing the wildtype allele. P. aeruginosa lipopolysaccharide-core oligosaccharide was identified as the bacterial ligand for epithelial cell ingestion; exogenous oligosaccharide inhibited bacterial ingestion in a neonatal mouse model, resulting in increased amounts of bacteria in the lungs. The authors concluded that CFTR may normally contribute to a host-defense mechanism that is important for clearance of P. aeruginosa from the respiratory tract.
Ernst et al. (1999) identified unique lipopolysaccharide structures synthesized by P. aeruginosa within CF patient airways. P. aeruginosa synthesized lipopolysaccharide with specific lipid A structures, indicating unique recognition of the CF airway environment. CF-specific lipid A forms containing palmitate and aminoarabinose were associated with resistance to cationic antimicrobial peptides and increased inflammatory responses, indicating that they are likely to be involved in airway disease.
Because mannose-binding lectin (MBL), encoded by the MBL2 gene (154545), is a key factor in innate immunity, and lung infections are a leading cause of morbidity and mortality in CF, Garred et al. (1999) investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, Garred et al. (1999) estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes.
Davies et al. (2000) found that MBL binds to Burkholderia cepacia, an important pathogen in patients with CF, and leads to complement activation, but that this was not the case for Pseudomonas aeruginosa, the more common colonizing organism in CF. Davies et al. (2000) suggested that patients with CF and mannose-binding lectin deficiency would be at a particularly high risk of B. cepacia colonization. The lack of binding to P. aeruginosa suggests that the effect of this organism on lung function in patients with MBL-deficient CF reflects a role for MBL, either in intercurrent infections with other organisms, or in the inflammatory process.
In an association study involving 112 patients with cystic fibrosis, Yarden et al. (2004) found that patients with the MBL2 A/O or O/O genotypes were more likely to have a more severe pulmonary phenotype than patients with the A/A genotype (p = 0.002). No association was found between the MBL2 genotype and the age at first infection with P. aeruginosa. Yarden et al. (2004) concluded that it is very likely that MBL2 is a modulating factor in cystic fibrosis.
Tarran et al. (2001) stated that there is controversy over whether abnormalities in the salt concentration or volume of airway surface liquid (ASL) initiate CF airway disease. Using CF mouse nasal epithelia, they showed that an increase in goblet cell number was associated with decreased ASL volume rather than abnormal Cl- concentration. Aerosolization of osmolytes in vivo failed to raise ASL volume. Osmolytes and pharmacologic agents were effective in producing isotonic volume responses in human airway epithelia but were typically short acting and less effective in CF cultures with prolonged volume hyperabsorption and mucus accumulation. These data showed that therapies can be designed to normalize ASL volume without producing deleterious compositional changes in ASL, and that therapeutic efficacy will likely depend on development of long-acting pharmacologic agents and/or an increased efficiency of osmolyte delivery.
Infertility
Oppenheimer et al. (1970) suggested that characteristics of cervical mucus may account for infertility in females with cystic fibrosis. Congenital bilateral absence of the vas deferens (CBAVD; 277180) is a usual cause of male infertility in cystic fibrosis. It also occurs with CFTR mutations in heterozygous state, especially when associated with the polymorphic number of thymidines in intron 8, specifically the 5T allele.
Carcinoma
Siraganian et al. (1987) pointed to adenocarcinoma of the ileum in 3 males with cystic fibrosis. The diagnosis was made between ages 29 and 34 years.
From a pancreatic adenocarcinoma developing in a 26-year-old patient with cystic fibrosis due to the phenylalanine-508 deletion, Schoumacher et al. (1990) established a cell line in which the cells showed morphologic and chemical characteristics typical of pancreatic duct cells and showed physiologic properties of CF cells. Schoumacher et al. (1990) suggested that the cell line, which had been stable through more than 80 passages over a 2-year period, could serve as a continuous cell line for studies of the CF defect. Bradbury et al. (1992) demonstrated that the CFTR protein is involved in cAMP-dependent regulation of endocytosis and exocytosis. In a study of pancreatic cancer cells derived from a CF patient, they found that plasma membrane recycling did not occur until normal CFTR was provided.
Neglia et al. (1995) performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from population-based data on the incidence of cancer. They also analyzed proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. The final results indicated that although the overall risk of cancer in patients with cystic fibrosis is similar to that of the general population, there is an increased risk of digestive tract cancers. They recommended that persistent or unexplained gastrointestinal symptoms in CF patients should be carefully investigated.
Patients with cystic fibrosis have altered levels of plasma fatty acids. Affected tissues from cystic fibrosis knockout mice show elevated levels of arachidonic acid and decreased levels of docosahexaenoic acid. Freedman et al. (2004) performed studies of fatty acids in nasal and rectal biopsy specimens, nasal epithelial scrapings, and plasma from 38 patients with cystic fibrosis, and found alterations in fatty acids similar to those in the knockout mice.
Other Features
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).
Recessive inheritance of cystic fibrosis was first shown clearly by Lowe et al. (1949). Roberts (1960) collected family data which appeared to him inconsistent with the quarter ratio expected of a recessive trait. Bulmer (1961) pointed out, however, that when proper correction is made for ascertainment bias, the observed proportions may agree with those expected for a recessive trait.
Rather than estimating the frequency of the CF gene from the square root of the incidence figure, Danks et al. (1983) used the frequency of CF in first cousins. The estimate of gene frequency was 0.0281 as contrasted with 0.0198 (based on direct count). Danks et al. (1983) suggested that the disparity between the 2 estimates might be the existence of 2 gene loci, each with a frequency of 0.0140 for the CF gene and a heterozygote frequency of 1 in 36. Thus, in Victoria, Australia, 1 in 18 persons might be heterozygous at one or the other locus. Later, however, the authors published a retraction and concluded that they had no evidence of more than 1 locus.
For risk analysis in cystic fibrosis, Edwards and Miciak (1990) proposed a simple procedure called the 'slash sheet.' They pointed out that the various methods of estimating genetic risk fall into 2 main groups: first, enumerating all possibilities and excluding those inconsistent with the tests, a simple procedure in small families, and second, using conditional arguments. The latter approach uses Bayes theorem. The former approach, Edwards and Miciak (1990) pointed out, follows a procedure advanced in 1654 by Pascal, following correspondence with Fermat, on the problem of the Chevalier de Mere, now known as the 'problem of points.' Two noblemen were gambling, and, while one was winning, the other was called away and the game was abandoned. How should the stakes be divided? Edwards and Miciak (1990) noted that 'genetic risk is merely an unfinished game of chance.'
See Hodge et al. (1999) for a discussion of calculation of CF risk in a fetus with 1 identified mutation in CFTR and echogenic bowel.
Park et al. (1987) concluded that CF is distal to and on the 5-prime side of MET. They determined this by in situ hybridization on metaphase and prometaphase chromosomes of normal lymphocytes as well as lymphoblastoid cells containing a t(5;7)(q35;q22). Normal cells showed clustering of MET grains to 7q31. Furthermore, in the lymphoblastoid cell line, there was significant labeling within the 5q+ chromosome, confirming that MET is located distal to 7q22 with most grains clustered at 7q31. Somatic cell hybrids containing the derivative 7 showed on Southern analysis that the 3-prime portion of the MET gene, but not the 5-prime portion, was located there; thus, MET is at the translocation breakpoint. Studies in another cell line with a 7q32 translocation breakpoint indicated that MET is located at or proximal to 7q32. A break at this site was accompanied by loss of 3 markers within 1 cM of CF, suggesting that if MET is at the breakpoint on 7q31, CF is located distally.
In the course of studying a case of cystic fibrosis, Spence et al. (1988) discovered what appeared to be a case of uniparental disomy: the father did not contribute alleles to the propositus for markers near the CF locus or for centromeric markers on chromosome 7. High-resolution cytogenetic analysis was normal, and the result could not be explained by nonpaternity or a submicroscopic deletion. Uniparental disomy could be explained by various mechanisms such as monosomic conception with subsequent chromosome gain, trisomic conception followed by chromosome loss, postfertilization error, or gamete complementation. Patients with more than one genetic disorder might be suspected of having isodisomy, which should also be suspected in cases of an apparent new mutation leading to a recessive disorder when only 1 parent is heterozygous, and in cases of females affected with X-linked recessive disorders. Engel (1980) appears to have originated the concept of uniparental disomy and resulting isodisomy. Voss et al. (1988, 1989) also demonstrated uniparental disomy for chromosome 7 in a patient with cystic fibrosis.
Mayo et al. (1980) attempted to map the cystic fibrosis gene by study of CF x mouse cell hybrids and examination for production of the cystic fibrosis mucociliary inhibitor. The strongest chance of assignment was for chromosome 4. Scambler et al. (1985) found that the albumin locus labeled by a DNA clone did not segregate with CF or with any of 6 other chromosome 4 markers. They estimated that about half the length of chromosome 4 was accounted for by the markers used. Eiberg et al. (1984) found a hint of linkage to F13B (134580); the maximum lod score was 1.71 at a recombination fraction of 0.05 for males and females combined. Linkage with 56 other genetic markers was negative (Eiberg et al., 1984). Eiberg et al. (1985) showed that cystic fibrosis and paraoxonase (PON; 168820) are linked; the maximum lod score was 3.70 at theta = 0.07 in males and 0.00 in females.
Tsui et al. (1985) found that the CF locus is linked to that of a DNA marker which is also linked to the PON locus, which in turn by independent evidence is linked to CF, thus closing the circle. The DNA marker was provisionally called D0CRI-917. The interval between the marker and PON was about 5 cM and the interval between it and CF about 15 cM. Whether the order is marker--PON--CF or PON--marker--CF was not certain; the former order was favored by 9:5 odds. Knowlton et al. (1985) reported that the anonymous probe D0CRI-917, linked to CF with about 15% recombination, is located on chromosome 7. White et al. (1985) showed very tight linkage to the MET oncogene (164860), which was assigned to the midportion of 7q. Wainwright et al. (1985) reported tight linkage also to the gene for another anonymous DNA probe, pJ3.11, which was assigned to 7cen-7q22. The closely linked probes pJ3.11 and MET are sufficiently informative to permit carrier detection in 80% of families in which there is a living CF child and unaffected sibs (Farrall et al., 1986). Scambler et al. (1985) showed that the COL1A2 gene (120160) is linked to CF (maximum lod for the sexes combined = 3.27 at a male recombination fraction of 0.08 and a female recombination fraction of 0.15.) PON and CF show recombination frequency of about 10%. CF is about 10 cM from both TCRB (see 186930) and COL1A2. TCRB and COL1A2 are not closely linked; thus, CF lies between them in the proximal part of 7q22. Wainwright et al. (1986) presented linkage data for COL1A2 versus CF (lod = 3.58 at theta = 0.10), TCRB versus CF (lod = 2.20 at theta = 0.15) and TCRB versus PON (all lods negative). Based on combined linkage data from 50 informative 2-generation families, Buchwald et al. (1986) concluded that CF is 19 cM from COL1A2, which is located at 7q21.3-q22.1. COL1A2 is closely linked to D7S15 and to PON. The probable order is COL1A2--D7S15--PON--CF. The regional localization of CF is 7q22.3-q23.1. Linkage of cystic fibrosis to various DNA markers and/or classical markers was reported in a series of articles by Beaudet et al. (1986), White et al. (1986), Bowcock et al. (1986), Farrall et al. (1986), Tsui et al. (1986), Spence et al. (1986), and Watkins et al. (1986). In Amish/Mennonite/Hutterite kindreds, Klinger et al. (1986) and Watkins et al. (1986) found close linkage with markers on chromosome 7, consistent with locus homogeneity for the defect causing CF in the populations that had been examined to date.
Estivill et al. (1987) identified a candidate for the cystic fibrosis locus by using a 'rare-cutter cosmid library.' They found a genomic region with the characteristics of an HTF island in high linkage disequilibrium with CF. The fact that the sequence was conserved throughout mammalian evolution strengthens the view that this is the CF gene. HTF islands, standing for HpaII tiny fragments, have a sequence length of between 500 and 1000 bp and often include the first exons as well as upstream sequences 5-prime to coding genes (Bird, 1986; Brown and Bird, 1986). These HTF islands are regions of DNA rich in the nonmethylated dinucleotide CpG and contain clusters of sites for CpG-methylation-sensitive restriction enzymes. (There are about 30,000 HTF islands in the human genome.) Estivill et al. (1987) stated that 94% of the chromosomes are of haplotype B, which is present in only 34% of the chromosomes in the general population. In 127 Italian families, Estivill et al. (1988) studied linkage disequilibrium of markers at the locus containing the CpG-enriched methylation-free island designated D7S23. In a search for deletions by means of field inversion gel electrophoresis (FIGE), Morreau et al. (1988) analyzed DNA from 10 cystic fibrosis patients representing 19 different CF chromosomes. No differences were detected after digestion of the samples with 2 different restriction enzymes and hybridization with 4 different probes. The authors estimated that the percentage of deletions occurring within the CF region is less than 15.2% (95% confidence interval, N = 19). The fact that no patient with a combination of cystic fibrosis and a genetic syndrome due to a second affected locus in close vicinity to the CF locus has been described suggests that deletions are rare. Beaudet et al. (1989) found strong linkage disequilibrium between the CF locus and closely linked markers on chromosome 7. By in situ hybridization Duncan et al. (1988) mapped 2 DNA sequences closely linked to the CF locus to 7q31.3-q32. This is a more distal location than had been inferred from previous data.
Using cystic fibrosis and published CF haplotypes as the test bed, Collins and Morton (1998) illustrated how allelic association can be efficiently combined with linkage evidence to identify a region for positional cloning of a disease gene.
For an extensive discussion of the molecular genetics of cystic fibrosis and a listing of allelic variants of the CFTR gene, see 602421. There is great variability of pulmonary phenotype and survival in cystic fibrosis, even among patients who are homozygous for the most prevalent mutation in the CFTR gene, delF508 (602421.0001).
Modifier Genes of Cystic Fibrosis
Although environmental influences may modify clinical disease in CF, additional genetic variation (i.e., modifier genes) may contribute to the expression of the final phenotype. For a review of possible modifier genes, see Shanthikumar et al. (2019). Select examples follow:
---Transforming Growth Factor, Beta-1
Drumm et al. (2005) studied variants of 10 genes previously reported as modifiers in cystic fibrosis in 2 studies with different patient samples. They first tested 808 patients who were homozygous for the delF508 mutation and were classified as having either severe or mild lung disease. Significant allelic and genotypic associations with phenotype were seen only for TGFB1 (190180), the gene encoding transforming growth factor beta-1, particularly the -509 and codon 10 polymorphisms. The odds ratio was about 2.2 for the highest-risk TGFB1 genotype (codon 10 CC; 190180.0007) in association with the phenotype of severe lung disease. In the replication (second) study, Drumm et al. (2005) tested 498 patients, with various CFTR genotypes and a range of values for forced expiratory volume in 1 second (FEV1), for an association of the TGFB1 codon 10 CC genotype with low FEV1. This replication study confirmed the association of the TGFB1 codon 10 CC genotype with more severe lung disease.
In a study of 1,019 Canadian pediatric CF patients, Dorfman et al. (2008) found a significant association between earlier age of first P. aeruginosa infection and MBL2 (154545) deficiency (onset at 4.4, 7.0, and 8.0 years for low, intermediate, and high MBL2 groups according to MBL2 genotype, respectively; p = 0.0003). This effect was amplified in patients with the high-producing genotypes of TGFB1, including variant C of codon 10. MBL2 deficiency was also associated with more rapid decline of pulmonary function, most significantly in those homozygous for the high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1 affected the modulation of age of onset by MBL2, there was no significant direct impact of TFGB1 codon 10 genotypes alone. The findings provided evidence for a gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGFB1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
Using quantitative transmission disequilibrium testing of 472 CF patient/parent trios, Bremer et al. (2008) found significant transmission distortion of 2 TGFB1 SNPs, -509 (rs1800469) and codon 10 (rs1982073), when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. A 3-SNP haplotype (CTC) composed of the -509 SNP C allele, the codon 10 T allele, and a 3-prime SNP rs8179181 C allele was highly associated with increased lung function in patients grouped by CFTR genotype. Bremer et al. (2008) concluded that TGFB1 is a modifier of CF lung disease, with a beneficial effect of certain variants on the pulmonary phenotype.
Epithelial Sodium Channel Subunits
Nonclassic forms of CF have been associated with mutations that reduce but do not eliminate the function of the CFTR protein. Mekus et al. (1998) described a patient with a nonclassic CF phenotype in whom no CFTR mutations could be found. Groman et al. (2002) assessed whether alteration in CFTR function is responsible for the entire spectrum of nonclassic CF phenotypes. Extensive genetic analysis of the CFTR gene was performed in 74 patients with nonclassic CF. Furthermore, they evaluated 2 families that each included a proband without identified CFTR mutations and a sib with nonclassic CF to determine whether there was linkage to the CFTR locus and to measure the extent of CFTR function in the sweat gland and nasal epithelium. Of the 74 patients studied, Groman et al. (2002) found that 29 had 2 mutations in the CFTR gene (i.e., were either homozygous or compound heterozygous at the CFTR locus), 15 had 1 mutation, and 30 had no mutations. A genotype of 2 mutations was more common among patients who had been referred after screening for a panel of common CF-causing mutations that had identified 1 mutation than among those who had been referred after screening had identified no such mutations. Comparison of clinical features and sweat chloride concentrations revealed no significant differences among patients with 2, 1, or no CFTR mutations. Haplotype analysis in the 2 families in which 2 sibs had nonclassic CF showed no evidence of linkage to CFTR. Although each of the affected sibs had elevated sweat chloride concentrations, measurements of cAMP-mediated ion and fluid transport in the sweat gland and nasal epithelium demonstrated the presence of functional CFTR. These sibs were later found to have bronchiectasis with elevated sweat chloride (211400) and biallelic mutation in the SCNN1B gene (600760). Groman et al. (2002) concluded that factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic CF caused by CFTR dysfunction.
Stanke et al. (2006) genotyped 37 delF508 homozygous sib pairs for markers on chromosome 12p13, encompassing the epithelial sodium channel (ENaC) subunit A (SCNN1A; 600228) and TNF-alpha receptor (TNFRSF1A; 191190) genes, and chromosome 16p12, encompassing the SCNN1B (600760) and SCNN1G (600761) genes, as potential CF disease modifiers. Transmission disequilibrium was observed at SCNN1G and association with CF phenotype intrapair discordance was observed at SCNN1B. Family-based and case-control analyses and sequencing uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Stanke et al. (2006) suggested that the SCNN1B, SCNN1G, and TNFRSF1A genes may be modulators of CF disease by affecting changes in airway surface liquids and host inflammatory responses.
Fajac et al. (2008) screened the SCNN1B gene in 55 patients with idiopathic bronchiectasis (see 211400) who had 1 or no mutations in the CFTR gene and identified heterozygosity for 3 missense mutations in the SCNN1B gene (see, e.g., 600760.0015) in 5 patients, 3 of whom also carried a heterozygous mutation in CFTR (602421.0001 and 602421.0086). 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.
Viel et al. (2008) analyzed the SCNN1B and SCNN1G genes in 56 adult patients with classic CF and discordance between their respiratory phenotype and CFTR genotype, including 38 patients with a severe genotype and an unexpectedly mild lung phenotype, and 18 patients with a mild genotype and severe lung phenotype. Three patients carried at least 1 missense mutation in SCNN1B or SCNN1G, but analysis of sodium channel function by nasal potential difference (PD) measurements did not support that the variants were functional. Viel et al. (2008) concluded that variation in SCNN1B and SCNN1G genes do not modulate disease severity in the majority of CF patients.
Azad et al. (2009) identified several rare SCNN1A polymorphisms with an increased incidence in patients with a cystic fibrosis-like phenotype and 1 or no CFTR mutations versus controls, including several patients with no CFTR mutation who were heterozygous for a hyperactive variant (W493R; 600228.0007). The authors hypothesized that given the CF-carrier (3.3%) and the W493R-carrier (3.1%) frequency in some populations, there ma be a polygenic mechanism of disease involving CFTR and SCNN1A in some patients.
Mutesa et al. (2009) analyzed the CFTR gene in 60 unrelated Rwandan children who had CF-like symptoms and identified heterozygosity for a CFTR mutation in 5 patients (none were homozygous). Sequencing of the ENaC subunits revealed heterozygous mutations in the SCNN1A and SCNN1B genes in 4 patients, respectively, whereas the remaining patient was heterozygous for a mutation in both SCNN1B and SCNN1G. Among the 55 patients who were negative for mutation in CFTR, only polymorphisms were found in the ENaC genes. Mutesa et al. (2009) concluded that some cases of CF-like syndrome in Africa may be associated with mutations in CFTR and ENaC genes.
Associations Pending Confirmation
---Fc Gamma Receptor IIa
In 69 Italian patients with CF due to homozygosity for the delF508 mutation in the CFTR gene (602421.0001), 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.
---Leptin
Mekus et al. (2003) examined modifying factors in CF by studying 34 highly concordant and highly discordant delF508 homozygous sib pairs selected from a group of 114 pairs for extreme disease phenotypes by nutritional and pulmonary status. They were typed for SNPs and short tandem repeat polymorphisms (STRPs) in a 24-cM CFTR-spanning region. Allele frequencies differed significantly at D7S495, located within a 21-cM distance 3-prime of CFTR, comparing concordant mildly affected, concordant severely affected, and discordant sib pairs. A rare haplotype of 2 SNPs within the leptin gene promoter (LEP; 164160) was found exclusively among the concordant mildly affected pairs. All concordant sib pairs shared the paternal delF508 chromosome between CFTR and D7S495, while the cohort of discordant sib pairs inherited equal proportions of recombined and nonrecombined parental chromosomes. Mekus et al. (2003) concluded that disease manifestation in CF is modulated by loci in the partially imprinted region 3-prime of CFTR that determine stature, food intake, and energy homeostasis, such as the Silver-Russell syndrome (180860) candidate gene region and LEP.
---Tumor Necrosis Factor/Mannose-Binding Lectin 2
Buranawuti et al. (2007) determined the genotype of 4 variants of 3 putative CF modifier genes (TNF-alpha-238; TNF-alpha-308, 191160.0004; TGF-beta-509; and MBL2 A/O) in 3 groups of CF patients: 101 children under 17 years of age, 115 adults, and 38 nonsurviving adults (21 deceased and 17 lung transplant after 17 years of age). Genotype frequencies among adults and children with CF differed for TNF-alpha-238 (G/G vs G/A, p = 0.022) and MBL2 (A/A vs O/O, p = 0.016), suggesting that MBL2 O/O is associated with reduced survival beyond 17 years of age, whereas TNF-alpha-238 G/A appears to be associated with an increased chance of surviving beyond 17 years of age. When adults with CF were compared to nonsurviving adults with CF, genotype frequencies of both genes differed (TNF-alpha 238 G/G vs G/A, p = 0.0015; MBL2 A/A vs O/O, p = 0.009); the hazard ratio for TNF-alpha-238 G/G versus G/A was 0.25 and for MLB2 O/O versus A/A or A/O was 2.5. Buranawuti et al. (2007) concluded that TNF-alpha-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of survival in patients with CF.
---Interferon-related Developmental Regulator 1
To identify genetic modifiers of lung disease severity in cystic fibrosis, Gu et al. (2009) performed a genomewide single-nucleotide polymorphism scan in 1 cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 (603502) as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone deacetylase-dependent transcriptional coregulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-null mice showed blunted effector function, associated with decreased NF-kappa-B p65 (RELA; 164014) transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease--a phenotype primarily dependent on hematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. Gu et al. (2009) concluded that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.
---Dynactin 4
Emond et al. (2012) used exome sequencing and an extreme phenotype study design to discover genetic variants influencing Pseudomonas aeruginosa infection in cystic fibrosis. Forty-three individuals with early age of onset of chronic P. aeruginosa infection (all below the tenth percentile of age at onset), and the 48 oldest individuals who had not reached chronic P. aeruginosa infection (all past the mean age of onset) were sequenced. After Bonferroni adjustment, a single gene, DCTN4, was significantly associated with time to chronic P. aeruginosa infection (naive P = 2.2 x 10(-6); adjusted P = 0.025). Twelve of the 43 individuals in the early extreme sample carried a missense variant in DCTN4, 9 a phe349-to-leu substitution (F349L; rs11954652) and 3 a tyr270-to-cys substitution (Y270C; rs35772018). None of the 48 individuals in the late P. aeruginosa extreme sample had either missense variant. Subsequently, 696 individuals with varied CFTR genotypes were studied. Seventy-eight participants were heterozygous and 9 were homozygous for the F349L (614758.0001) mutation; 15 were heterozygous for the Y270C (614758.0002) mutation; 1 individual was heterozygous for both mutations. The presence of at least 1 DCTN4 missense variant was significantly associated with both early age of first P. aeruginosa-positive culture (p = 0.01, hazard ratio = 1.4) and with early age of onset of chronic P. aeruginosa infection (p = 0.004, hazard ratio = 1.9). The risk was highest in individuals with less selective bias toward a P. aeruginosa-negative history, i.e., children enrolled before 1.5 years of age and 103 enrollees who participated in the study despite a history of P. aeruginosa-positive cultures. No significant interaction was found between CFTR genotypes and DCTN4 mutations, although power to detect such an interaction was low.
---Alpha-1-Antitrypsin
Because proteinase-antiproteinase imbalances are common in both CF and alpha-1-antitrypsin deficiency (613490), Meyer et al. (2002) investigated the hypothesis that the common AAT deficiency alleles PI Z (107400.0011) and PI S (107400.0013) contribute to pulmonary prognosis in CF. In 269 CF patients from southern Germany, they determined the serum concentrations of AAT (107400) and C-reactive protein (CRP; 123260) by nephelometry and screened for the common AAT deficiency alleles by PCR and restriction enzyme digest. The onset of chronic bacterial colonization by P. aeruginosa was correlated with the AAT phenotypes PI MM, PI MS, and PI MZ. Only 3 of 9 (33%) CF patients diagnosed with either PI MS or PI MZ had developed chronic P. aeruginosa lung infection earlier in their lives; the remaining 6 PI MS or PI MZ patients showed a later onset of chronic P. aeruginosa lung infection. The results suggested that PI MS and PI MZ are not associated with a worse pulmonary prognosis in CF.
Wine (1992) pointed out that CFTR mutations associated with pancreatic sufficiency, milder pulmonary disease, and improved sweat gland function are associated with residual CFTR chloride-ion channel function. He questioned the disruptive effects proposed for the delF508 mutation because variation in homozygotes for this mutation is very large. At the same time, those homozygous for stop codons have been severely affected, showing pancreatic insufficiency and pulmonary function values (FEV1) in the same range as those of delF508 subjects. Disruptive effects of delF508 would be expected to give rise to a dominant pattern of inheritance. Wine (1992) concluded that the observations are consistent with the recessive nature of CF and with the likelihood that gene or protein replacement therapy for CF will be effective on their own, without requiring concomitant silencing of the delF508 gene. Sheppard et al. (1993) found that some CFTR mutations, such as delF508, which disrupt normal processing and hence are missing from the apical membrane, generate no chloride current and are associated with severe disease. Other mutants, such as R117H (602421.0005), R334W (602421.0034), and R347P (602421.0006), which are correctly processed and retain significant apical chloride channel function, are associated with a milder form of the disease. Thus, the CF genotype determines the biochemical abnormality, which determines the clinical phenotype. Because these 3 'mild' mutants have normal regulation, interventions designed to increase the activity of mutant CFTR may have therapeutic efficacy in patients with these mutations. Studying 267 children and adolescents with CF who were regularly seen at the same center, Kubesch et al. (1993) found that the age-specific colonization rates with Pseudomonas aeruginosa were significantly lower in pancreatic sufficient than in pancreatic insufficient patients. The missense and splice site mutations that were 'mild' CF alleles with respect to exocrine pancreatic function were also 'low risk' alleles for the acquisition of P. aeruginosa. On the other hand, the proportion of P. aeruginosa-positive patients increased most rapidly in the pancreatic insufficient delF508 compound heterozygotes who were carrying a termination mutation in the nucleotide binding fold-encoding exons.
Kulczycki et al. (2003) stated that their oldest patient was a 71-year-old white male who was diagnosed with CF at the age of 27 years because of recurrent nasal polyposis, elevated sweat sodium and chloride, and a history of CF in his 20-year-old sister. The man was married but childless, and practiced as an attorney. Urologic examination revealed CBAVD. Nutritional and pulmonary status were almost normal. At the age of 60 years, genetic testing indicated 2 mutations in the CFTR gene: his1282 to ter (H1282X; 602421.0129), which is associated with severe CF, and ala445 to glu (A445E; 602421.0130), which is associated with mild CF.
Frizzell (1987) pointed out that cystic fibrosis is of interest to neuroscientists because it appears to be a disease of ion channels. It is apparently not the conduction properties of ion channels that are affected, but rather their gating by chemical agonists. These conductance pathways appear to be unique to epithelial cells in which salt and water transport rates are governed by cyclic AMP and calcium-dependent regulatory processes.
Decrease in fluid and salt secretion is responsible for the blockage of exocrine outflow from the pancreas and the accumulation of heavy dehydrated mucous in the airways. In sweat glands, salt reabsorption is defective. This is the basis of the folkloric anecdote that the midwife would lick the forehead of the newborn and, if the sweat tasted abnormally salty, predict that the infant was destined to die of pulmonary congestion and its side effects. Quinton (1983) and Knowles et al. (1983) first suggested that the primary defect of cystic fibrosis may be in chloride transport. Widdicombe et al. (1985) demonstrated a cyclic AMP-dependent transepithelial chloride current in normal but not CF epithelia. The pathophysiology of cystic fibrosis, specifically the impermeability of epithelia to chloride ion, was reviewed by Welsh and Fick (1987).
Landry et al. (1989) purified several proteins from kidney and trachea that exhibit chloride channel activity when they are reconstituted into artificial phospholipid bilayer membranes. One or more of these proteins may turn out to be all or part of the secretory chloride channel that is defective in CF. Using antibodies against CFTR peptides, Marino et al. (1991) demonstrated that the CFTR molecule is located in and confined to the apical domain of pancreatic centroacinar and intralobular duct cells. From this they concluded that the proximal duct epithelial cells play a key role in the early events leading to pancreatic insufficiency in CF and that apical chloride transport by these cells is essential for normal pancreatic secretory function. Jetten et al. (1989) created a stable human airway epithelial cell line by retroviral transformation of CF airway epithelium. They found that it maintains the defect in the secretory chloride channel. Rich et al. (1990) expressed the CFTR gene in cultured cystic fibrosis airway epithelial cells and assessed chloride ion channel activation in single cells by means of a fluorescence microscopic assay and a patch-clamp technique. In cells from patients with CF, expression of the CFTR gene but not of the mutant form corrected the chloride ion channel defect. Since there is no animal model for CF, the authors viewed the cell line as very important in studies of the basic defect and for screening of candidate genes which would complement the defect and thus identify the site of the mutation. Bradbury et al. (1992) raised the question as to whether there may be more to the pathogenesis of cystic fibrosis than merely a defect in chloride passage across cell membranes and the concomitant defect in secretion of water.
Two hypotheses, 'hypotonic (low salt)/defensin' and 'isotonic volume transport/mucus clearance,' attempt to link defects in cystic fibrosis transmembrane conductance regulator-mediated ion transport to CF airways disease. Matsui et al. (1998) tested these hypotheses with planar and cylindrical culture models and found no evidence that the liquids lining airway surfaces were hypotonic or that salt concentrations differed between CF and normal cultures. In contrast, CF airway epithelia exhibited abnormally high rates of airway surface liquid absorption, which depleted the periciliary liquid layer and abolished mucus transport. The failure to clear thickened mucus from airway surfaces likely initiates CF airways infection. These data indicate that therapy for CF lung disease should not be directed at modulation of ionic composition, but rather at restoring volume (salt and water) on airway surfaces.
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.
Kravchenko et al. (2008) showed that a bacterial small molecule, N-(3-oxo-dodecanoyl) homoserine lactone (C12), selectively impairs the regulation of NF-kappa-B (see 164011) functions in activated mammalian cells. The consequence is specific repression of stimulus-mediated induction of NF-kappa-B-responsive genes encoding inflammatory cytokines and other immune regulators. Kravchenko et al. (2008) concluded that their findings uncovered a strategy by which C12-producing opportunistic pathogens such as P. aeruginosa attenuate the innate immune system to establish and maintain local persistent infection in humans, for example, in cystic fibrosis patients.
Boue et al. (1986) reported on prenatal diagnostic studies in 200 pregnancies with a presumed 1-in-4 risk of recurrence of cystic fibrosis. The method involved measurement of total enzymes and isoenzymes of gamma-glutamyl-transpeptidase, aminopeptidase M, and alkaline phosphatase in amniotic fluid in the second trimester. The recurrence rate of cystic fibrosis was 22.5% in 147 cases in which the index case had cystic fibrosis without meconium ileus at birth but was 47.5% when the index case had meconium ileus. The authors speculated on the mechanism of the 50% recurrence rate and favored the view that 1 parent was in fact a homozygote for a mild allele. With use of their method, the authors suggested 98% accuracy in prenatal diagnosis of cystic fibrosis. Allan et al. (1981), Super (1987), and Boue et al. (1986) found that in families in which a CF child did not have meconium ileus the observed recurrence rate agreed with the expected 1-in-4 risk, but that in families with a history of meconium ileus in the index case the recurrence rate was much higher, 43.7% in the study of Boue et al. (1986). Mornet et al. (1989) found different haplotype associations in the 2 types of families. A distortion of the segregation ratio was suggested to explain the high recurrence rate. Estivill et al. (1987) pointed out that individuals with haplotypes A and C as determined by their cosmid library, whether homozygous or heterozygous, have a considerably reduced risk of being carriers as compared to the 1 in 20 average risk in the British population. On the other hand, a homozygote for haplotype B had a risk of about 1 in 7 of being a carrier. It appears that about 85% of cases of CF in northern Europeans have 1 particular haplotype and the rest a second haplotype. CF with or without meconium ileus may be different entities. Baxter et al. (1988) stated that the meconium ileus form of CF is often lethal so that families with this form are underrepresented in linkage studies. On the other hand, couples who seek prenatal diagnosis often have had children with this problem. Harris et al. (1988) found that 30 of 37 British CF families were sufficiently informative with 3 RFLP probes to enable prenatal diagnosis. They also used linkage analysis to exclude CF in 2 cases in which diagnosis of the disease was equivocal in the sib of an affected child.
Strain et al. (1988), Krawczak et al. (1988), and Beaudet et al. (1989) discussed the use of linkage disequilibrium between CF and DNA markers in genetic risk calculation. Handyside et al. (1992) achieved preimplantation diagnosis. In vitro fertilization techniques were used to recover oocytes from each of 3 women and fertilize them with the husband's sperm. Both members of the 3 couples carried the delF508 mutation. Three days after insemination, embryos in the cleavage stage underwent biopsy with removal of 1 or 2 cells for DNA amplification and analysis. In 2 of the women the oocytes produced noncarrier, carrier, and affected embryos. Both couples chose to have 1 noncarrier embryo and 1 carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes. Curnow (1994) used cystic fibrosis to illustrate how, in genetic counseling, one can calculate carrier risk for recessive diseases when not all the mutant alleles are detectable. Dean (1995) reviewed the 5 main methods used for detecting mutations at the time.
Savov et al. (1995) demonstrated the presence of 2 different mutations carried by the same CF allele in 4 out of 44 Bulgarian CF patients during a systematic search of the entire coding sequence of the CFTR gene. Two of the double mutant alleles include 1 nonsense and 1 missense mutation, and although the nonsense mutation could be considered to be the main defect, the amino acid substitutions are candidates for disease-causing mutations as well. Savov et al. (1995) suggested that double mutant alleles may be more common than expected and could account for some of the problems in phenotype-genotype correlations. Stern (1997) reviewed the diagnosis of cystic fibrosis. He presented a table of conditions, all readily distinguishable from cystic fibrosis, that can cause moderately elevated sweat electrolytes. With mutation analysis, in approximately 1% of cases no abnormal gene can be found and in about 18% more only 1 abnormal gene will be identified. Stern (1997) pointed out, however, that even if both genes were abnormal, the patient could have an ameliorating or neutralizing second mutation elsewhere. For example, patients homozygous for delF508 (602421.0001) have normal sweat electrolyte concentrations if a second mutation, R553Q (602421.0121), is also present.
Screening
Under the chairmanship of Beaudet and Kazazian (1990), a workshop at the National Institutes of Health laid down guidelines concerning screening for the cystic fibrosis gene. The following points were emphasized: screening should be voluntary, and confidentiality must be assured; screening requires informed consent; providers of screening services have an obligation to ensure adequate education and counseling; quality control in all aspects of testing is required; and there should be equal access to testing.
Newborn babies with CF have abnormally high levels of immunoreactive trypsin (IRT) in serum, which has been the basis for a screening test. Hammond et al. (1991) reported on the results of a Colorado statewide test of the feasibility and efficacy of measuring immunoreactive trypsinogen in blood spots to screen for neonatal cystic fibrosis. They found an incidence of cystic fibrosis of 1 in 3,827 (0.26 per 1,000), with 3.2 newborns per 1,000 requiring repeat measurements. When adjusted for race and compliance with testing, the incidence among the white infants (1 in 2,521) was close to the expected incidence. They concluded that screening was feasible and could be implemented with acceptable rates of repeat testing and false positive and false negative results. Laroche and Travert (1991) found 9 F508 deletion heterozygotes among 149 infants with neonatal transitory mild hypertrypsinemia. Dumur et al. (1990) found an increased frequency of heterozygosity for the same mutation in adults with chronic bronchial hypersecretion.
Observing that many patients with cystic fibrosis are malnourished by the time the diagnosis is made, Farrell et al. (1997) sought to determine whether newborn screening and early treatment might prevent the development of nutritional deficiency. A total of 650,341 newborn infants were screened by measuring immunoreactive trypsinogen on dried blood spots (from April 1985 through June 1991) or by combining the trypsinogen test with DNA analysis (from July 1991 through June 1994). Of 325,171 infants assigned to an early-diagnosis group, cystic fibrosis was diagnosed in 74 infants, including 5 with negative screening tests. Excluding infants with meconium ileus, Farrell et al. (1997) evaluated nutritional status for up to 10 years by anthropometric and biochemical methods in 56 of the infants who received an early diagnosis and in 40 of the infants in whom the diagnosis was made by standard methods (the control group). Pancreatic insufficiency was managed with nutritional interventions that included high-calorie diets, pancreatic enzyme therapy, and fat-soluble vitamin supplements. The diagnosis of cystic fibrosis was confirmed by a positive sweat test at a younger age in the early-diagnosis group than in the control group (mean age, 12 vs 72 weeks). At the time of diagnosis, the early-diagnosis group had significantly higher height and weight percentiles and a higher head circumference percentile. The early-diagnosis group also had significantly higher anthropometric indices during the follow-up, especially the children of pancreatic insufficiency and those who were homozygous for the delta-F508 mutation. Dankert-Roelse and te Meerman (1997) raised the question of whether the time had not arrived for adoption of routine neonatal screening for cystic fibrosis.
Farrell et al. (2001) reported findings of the continuation of their longitudinal study of children with CF detected by neonatal screening or standard clinical methods (control). Because sequential analysis of nutritional outcome measures revealed significantly better growth in screened patients, the authors accelerated the unblinding of the control group and identified 9 additional CF patients. After each member of this cohort had been enrolled for at least 1 year, Farrell et al. (2001) performed another statistical analysis of anthropometric indices. They found that severe malnutrition persisted after delayed diagnosis of CF and questioned whether catch-up growth is possible.
Muller et al. (1998) studied 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. Seven of the 209 fetuses (3.3%) were subsequently given the diagnosis of cystic fibrosis. Muller et al. (1998) pointed out that this incidence is 84 times the estimated risk of cystic fibrosis in the general population, and concluded that screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography.
Boyne et al. (2000) demonstrated that of 88 neonates with transient hypertrypsinemia shown to carry a delta-F508 mutation, 20 (22%) carried a second CFTR mutation. In 45% of cases, the second mutation was R117H (602421.0005). Forty-one percent of delta-F508 heterozygous neonates with greater than 25 ng IRT/ml in the 27th day blood sample possessed a second mutation, compared to approximately 6% of those with less than 25 ng/ml. Boyne et al. (2000) concluded that the IRT level at 27 days is a useful marker to refine the risk of finding a second CFTR mutation in delta-F508 heterozygotes with hypertrypsinemia.
Castellani et al. (2001) studied 47 neonates with hypertrypsinemia and normal sweat chloride. Thirty-two of the newborns had 1 identified CFTR mutation. Further analysis by DGGE identified additional mutations in 14 of the 32 babies in whom a mutation had previously been found. In 1 case, 2 more CFTR gene mutations were identified. Mutations were identified in 8 of the 15 babies in whom a mutation had previously not been identified. Castellani et al. (2001) pointed out that it is impossible to predict the clinical outcome of these newborns and suggested that in some cases these findings might represent CFTR-related disease even in the presence of normal sweat chloride. They therefore advocated close clinical follow-up of neonates in this group.
Scotet et al. (2002) evaluated the prenatal detection of CF by ultrasound in more than 346,000 pregnancies in Brittany, France, where the incidence of CF is very high. The authors found that the incidence of CF in fetuses with echogenic bowel was 9.9%, significantly higher than in the general population. Only severe mutations were identified in these fetuses. The ultrasound examination enabled diagnosis of 11% of affected fetuses. Scotet et al. (2002) concluded that CF screening based on ultrasound examination is effective, particularly in populations where the disease is frequent.
Dequeker et al. (2009) provided an update on the best practice guidelines for the molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders, as established at a 2006 conference in Manchester, U.K. The report included methods for CFTR mutation testing, indications for CFTR testing, and guidelines for interpretation.
De Becdelievre et al. (2011) reported on an 18-year experience of documenting comprehensive CFTR genotypes and correlations with ultrasound patterns in a series of 694 cases of fetal bowel anomalies. A total of 30 CF fetuses and 8 cases compatible with CFTR-related disorders were identified. CFTR rearrangements were found in 5 of the 30 CF fetuses. A second rare mutation indicative of CF was found in 21.2% of fetuses carrying a frequent mutation. The frequency of CF among fetuses with no frequent mutation was 0.43%. Correlation with ultrasound patterns revealed a significant frequency of multiple bowel anomalies in CF fetuses. The association of at least 2 signs of bowel anomaly on ultrasound, including hyperechogenic bowel, loop dilatation, and/or nonvisualization of gallbladder, was observed in 14 of 30 CF fetuses (46.7%) as compared with 61 of 422 (14.5%) non-CF fetuses (P less than 10(-3)). The rare triad of hyperechogenic bowel, loop dilatation, and nonvisualization of the gallbladder was of the highest diagnostic value, with a likelihood ratio of 31.40. Fetuses demonstrating this triad of bowel anomalies should have extensive CFTR sequencing and a search for rearrangements, even if no common mutation is detected.
Hubbard et al. (1992) reported on the use of human deoxyribonuclease I produced by recombinant DNA techniques for cleaving DNA in the sputum of patients with cystic fibrosis and thereby reducing sputum viscosity. Improvement of lung function was documented.
Treatment of Fibrosing Colonopathy in Cystic Fibrosis
Smyth et al. (1994) described colonic strictures, later referred to as fibrosing colonopathy, in children with cystic fibrosis. The patients presented with intestinal obstruction and required surgical resection of a thickened and narrowed area of the colon. The only aspect of these children's management that had changed was a switch to new 'high strength' pancreatic enzyme preparations about 12 months previously. It was not clear whether the preparation was responsible for the problem or whether this was a part of the pathology of cystic fibrosis. In some instances, the clinical and radiologic features were suggestive of Crohn disease or an inflammatory colitis, but the histologic findings were strikingly different (Smyth, 1996). The stenoses, which are frequently long segment, result from submucosal thickening by fibrous connective tissue. This leads to intraluminal narrowing which occurs without a significant reduction in the external diameter of the colon. The epithelium is generally intact with very little inflammatory change in the affected areas. FitzSimmons et al. (1997) studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy that required colectomy for colonic strictures and compared the patients with 105 controls (mean age 5.2 years) who were other patients with cystic fibrosis matched for age at the time of surgery and who did not have fibrosing colonopathy. They found that the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with the dose of 0 to 24,000 units per kilogram per day, was 10.9, and relative risk associated with a dose of more than 50,000 units per kilogram per day was 199.5. The findings were considered to support the recommendation that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.
Potentiators
On January 31, 2012, the FDA approved Kalydeco, formerly VX-770 (ivacaftor), for use in cystic fibrosis patients with the G551D mutation (602421.0013), as reported by Ledford (2012).
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 treatment and placebo with respect to mean absolute improvement in the percentage of predicted 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.
Taylor-Cousar et al. (2017) performed a phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial, evaluating combination therapy with tezacaftor and ivacaftor in cystic fibrosis patients 12 years of age or older who were homozygous for the CFTR F508del mutation (602421.0001). Patients were randomly assigned in a 1:1 ratio to receive either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or matched placebo for 24 weeks. The primary end point was the absolute change in the percentage of the predicted forced expiratory volume in 1 second (FEV1) through week 24; relative change in the percentage of the predicted FEV1 through week 24 was a key secondary end point. Of the 510 patients who underwent randomization, 509 received tezacaftor-ivacaftor or placebo, and 475 completed 24 weeks of the trial regimen. The mean FEV1 at baseline was 60.0% of the predicted value. The effects on the absolute and relative changes in the percentage of the predicted FEV1 in favor of tezacaftor-ivacaftor over placebo were 4.0 percentage points and 6.8%, respectively (p less than 0.001 for both comparisons). The rate of pulmonary exacerbation was 35% lower in the tezacaftor-ivacaftor group than in the placebo group (p = 0.005). The incidence of adverse events was similar in the 2 groups, but serious adverse events were less frequent in the tezacaftor-ivacaftor (12.4%) than with placebo (18.2%).
To evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, Rowe et al. (2017) conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial in 248 cystic fibrosis patients 12 years of age or older who were heterozygous for the F508del mutation (602421.0001) and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to 1 of 6 sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor monotherapy, or placebo. The primary endpoint was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (p less than 0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (less than 1%).
Middleton et al. (2019) conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. Among 403 patients, elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (p less than 0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the treatment group. Middleton et al. (2019) concluded that elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective.
McGarry (2020) requested data on racial and ethnic distribution of CF patients enrolled in the trial described by Middleton et al. (2019). Jain et al. (2020) responded that 16 patients were Hispanic and 6 were black, and that 4 persons from each of those groups was assigned to the elexacaftor-tezacaftor-ivacaftor treatment group. Jain et al. (2020) noted that, although these numbers were insufficient for robust analysis, both ethnic group and CFTR modulator use are captured in the Cystic Fibrosis Foundation Patient Registry and other data repositories, providing additional opportunities to evaluate ethnicity-specific outcomes.
Amphotericin B
Muraglia et al. (2019) reported that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored bicarbonate secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na(+),K(+)-ATPase (see 182310), indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Muraglia et al. (2019) concluded that unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.
Gene Therapy
Rosenfeld et al. (1992) evaluated the direct transfer of the normal CFTR gene to airway epithelium using a replication-deficient recombinant adenovirus (Ad) vector containing normal human CFTR cDNA (Ad-CFTR). Two days after in vivo intratracheal introduction of Ad-CFTR in cotton rats, in situ analysis demonstrated human CFTR gene expression in lung epithelium. Northern analysis of lung RNA revealed human CFTR transcripts for up to 6 weeks. Human CFTR protein was detected in epithelial cells using anti-human CFTR antibody 11 to 14 days after infection. While the safety and effectiveness remained to be demonstrated, these observations suggested the feasibility of in vivo CFTR gene transfer as therapy for the pulmonary manifestations of CF.
Hyde et al. (1993) illustrated the feasibility of gene therapy for the pulmonary aspects of CF in humans. They used liposomes to deliver a CFTR expression plasmid to epithelia of the airway and to alveoli deep in the lung, leading to the correction of the ion conductance defects found in the trachea of transgenic (cf/cf) mice. Yang et al. (1993) described a similar approach to the treatment of hepatobiliary disease of cystic fibrosis. In situ hybridization and immunocytochemical analysis of rat liver sections indicated that the endogenous CFTR gene is primarily expressed in the intrahepatic biliary epithelial cells. To target recombinant genes specifically to the biliary epithelium in vivo, Yang et al. (1993) infused recombinant adenoviruses expressing lacZ or human CFTR into the biliary tract through the common bile duct. Conditions were established for achieving recombinant gene expression in virtually all cells of the intrahepatic bile ducts in vivo. Expression persisted in the smaller bile ducts for the duration of the experiment, which was 21 days.
Crystal et al. (1994) administered a recombinant adenovirus vector containing the normal human CFTR cDNA to the nasal and bronchial epithelium of 4 individuals with CF. They found that the vector can express the CFTR cDNA in the CF respiratory epithelium in vivo. With doses up to 2 x 10(9) pfu, there was no recombination/complementation or shedding of the vector or rise of neutralizing antibody titers. At 2 x 10(9) pfu, a transient systemic and pulmonary syndrome was observed. The syndrome was thought to have been caused by vector-induced inflammation of the lower respiratory tract and was possibly induced by interleukin-6, which was found at high levels in the serum of a patient. Follow-up at 6 to 12 months demonstrated no long-term adverse effects. Crystal et al. (1994) concluded that correction of the CF phenotype in the airway epithelium might be achieved with this approach.
A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis by Knowles et al. (1995) yielded less encouraging results than those predicted by Crystal et al. (1994). Knowles et al. (1995) did not succeed in correcting the functional defects in nasal epithelium and local inflammatory responses limited the dose of adenovirus that could be administered to overcome the inefficiency of gene transfer.
Wilson (1995) reviewed gene therapy for cystic fibrosis. Transplantation of ex vivo manipulated stem cells was the concept of gene therapy used in ADA deficiency (102700). Wide distribution of possible cellular targets for gene therapy in the CF lung and the absence of a known lung epithelial stem cell suggested that an ex vivo approach to gene therapy would not be feasible. Therefore research focused on in vivo approaches for gene transfer that could conveniently be delivered into the airway via aerosols.
Yan et al. (2019) and Lee et al. (2021) reviewed the status of gene therapy for cystic fibrosis.
Attempting total ascertainment of cases in white children born alive in Ohio during the years 1950 through 1953, Steinberg and Brown (1960) estimated the phenotype frequency to be about 1 in 3,700, a value only about one-fourth that of some earlier estimates. Cystic fibrosis even at this lower estimate is the most frequent lethal genetic disease of childhood. The gene frequency was estimated to be about 0.016, and about 3% of white persons are heterozygotes.
Klinger (1983) found an incidence of 1 in 569 among 10,816 live births in the Old Order Amish of Holmes County, Ohio. The gene frequency was estimated to be at least 0.042. On the other hand, not a single case was found among 4,448 live births in the Geauga County, Ohio, Amish. In Connecticut, Honeyman and Siker (1965) arrived at higher phenotype frequency estimates of 1 in 489 (maximal) and 1 in 1,863 (minimal).
Bois et al. (1978) reported a frequency of at least 1 in 377 births in an area of Brittany, France. Scotet et al. (2002) retrospectively registered all 520 CF patients born in Brittany since 1960. The birthplace of the patients, the spectrum of CFTR mutations, and the spatial distribution of the mutations across Brittany were determined. The incidence of CF was 1 in 2,630, with a west/east gradient that was confirmed over time (1 in 2,071 in the west, 1 in 3,286 in the east). At the time of study, the incidence of CF was decreasing, mainly as a result of prenatal diagnosis. A mutation detection rate of 99.7% was obtained. Western Brittany presented a specific spectrum of mutations, whereas the eastern region showed a spectrum more similar to the overall picture in France.
In Italy, to estimate the incidence of CF, Romeo et al. (1985) used the increase in first- and second-cousin parentage, as compared with the general level of consanguinity indicated by the archive of consanguineous marriages maintained by the Catholic Church. The incidence was estimated to be about 1/2000. The data were consistent with a single gene locus; consanguinity would have been higher if more than one were present. The segregation ratio in 624 CF sibships was 0.252.
In Hutterite families with cystic fibrosis, Ober et al. (1987) found close linkage to chromosome 7 markers as in non-Hutterite families. Because 3 different chromosome 7 haplotypes carried the CF mutation in these families, they suggested that the CF gene may have been introduced into the Hutterite population by as many as 3 different ancestors. Fujiwara et al. (1989) confirmed these observations.
From studies in Caucasian families in Utah, Jorde and Lathrop (1988) concluded that fertility differences are unlikely to account for the observed Caucasian CF gene frequency. They compared 143 grandparent couples of Utah CF cases with 20 replicate sets of matched control couples drawn from the Utah Genealogical Database. Before ascertainment correction was applied, CF carriers appeared to manifest a significant fertility advantage over controls. After the correction formula (not used in previous studies) was applied, this difference disappeared. Also, no differences were found between carriers and controls in the length of intervals between births.
In the Hutterites, Klinger et al. (1990) demonstrated that 1 of the 3 previously identified CF haplotypes carries the phe508 deletion. The other 2 Hutterite CF haplotypes are generally rare in Caucasian populations and must carry different CF mutations. Thus, there must have been at least 3 original carriers of CF mutations among the founders of the Hutterite population. They found 1 Hutterite CF patient who had both of the haplotypes that do not carry the phe508 deletion.
From a study in Northern Ireland, Hill et al. (1989) concluded that the CF locus is in strong linkage disequilibrium with KM19 and Xv-2C, as it is in other Caucasian populations. These findings indicate that CF in northern European populations may have resulted from a single ancestral mutation. A further finding was preferential inheritance of the paternal CF allele (22 of 28) as opposed to the maternal CF allele (6 of 28) with no significant difference in the sex of the children inheriting these alleles. Cutting et al. (1989) concluded from the analysis of closely linked DNA marker haplotypes that the majority of CF mutations in the Caucasian population arose from a single mutational event. Similar analysis in American black families suggested that multiple mutant alleles are found in this population.
Although CF had been thought to be very rare in Arabs, Nazer et al. (1989) documented CF in 13 children in Saudi Arabia. El-Harith et al. (1998) reported that 6 mutations, detectable by PCR with subsequent restriction enzyme digestion, would allow detection of 70% of Saudi CFTR mutations.
Estivill et al. (1989) reported that in Spanish and Italian populations, deletion of phe508 is present in only 46.2% of CF chromosomes. In all cases, it occurred with haplotype 2, which accounts for about 75% of southern European CF chromosomes; thus, at least 2 independent mutations must have occurred on this haplotype. McIntosh et al. (1989) found a frequency of 74.4% for the phe508 deletion in Scotland. Colten (1990) indicated that one-third of the more than 15,000 patients listed in the registry of the North American National Cystic Fibrosis Foundation are older than 21 years.
Using PCR and hybridization with allele-specific oligonucleotides, Lemna et al. (1990) found the phe508 deletion in 75.8% of 439 cystic fibrosis chromosomes. The 3-base deletion was found in only 30.3% of cystic fibrosis chromosomes from Ashkenazi families. In 5 southern European populations (Albanian, Greek, Italian, Spanish, and Yugoslavian), Nunes et al. (1991) found that, apart from delF508, the most frequent mutations were G542X (602421.0009), 6.04%; R1162X (602421.0033), 3.61%; and N1303K (602421.0032), 3.24%. Of the 14 mutations tested, 7 others had frequencies of less than 1% and 4 mutations were not found at all.
Ten Kate et al. (1991) demonstrated that consanguinity, even if present, may be irrelevant: a family with 2 brothers with cystic fibrosis whose parents were consanguineous, being members of an isolated religious group, were found to have inherited different mutations from the parents. They presented a diagram relating the likelihood of 'autozygosity,' depending on gene frequency with consanguinity of various degrees.
In a systematic study of 365 CF chromosomes in the Celtic population in Brittany, Ferec et al. (1992) identified more than 98% of the cystic fibrosis gene mutations. By use of the denaturing gradient gel electrophoresis (DGGE) method, they detected 19 different CFTR mutations located in 9 exons. Nine new mutations were found.
Kerem et al. (1995) reported that the incidence of CF and the frequency of disease-causing mutations varies considerably among the Jewish ethnic subgroups in Israel. Among Ashkenazi Jews, the frequency of CF is 1:3300, which is similar to the frequency in most Caucasian populations. Among non-Ashkenazi Jews, the disease occurs at a similar frequency among Jews from Libya (1:2700), Georgia (1:2700), Greece and Bulgaria (1:2400), but is rare in Jews from Yemen (1:8800), Morocco, (1:15000), Iraq (1:32000), and Iran (1:39000). To that point, only 12 mutations had been identified in Israeli Jews, and this enabled the identification of 91% of the CF chromosomes in the entire Jewish CF population. However, in each Jewish ethnic group, the disease is caused by a different repertoire of mutations.
In a study in the Netherlands, de Vries et al. (1997) tested for the carrier frequency of the delta-F508 mutation by analyzing mouthwashes and matched blood samples from 11,654 blood donors from all over the country. They detected a delF508 carrier frequency of 1 in 42 (95% CI 1/37-1/47). By assuming that the relative frequency of the delF508 mutation among carriers and patients is comparable in the Netherlands, they estimated the overall CF carrier frequency as 1 in 32, significantly less than 1 in 25, the usual figure cited. An increase in carrier frequency with increasing distance from the northeastern region of the country was observed, thus confirming that there is a gradient in gene frequency with low frequencies in the northeastern part of the country and high frequencies in the southern part.
Brock et al. (1998) studied a total of 27,161 women enrolled in prenatal clinics in Scotland between 1990 and 1997. All 27,161 were screened for the delta-F508 (602421.0001), G551D (602421.0013), and G542X (602421.0009) mutations. In 14,360 women R117H was also measured. In addition, 183 patients with cystic fibrosis were studied for the presence of these mutations. Based on their data, the authors estimated that the incidence of CF in the Scottish population is 1 in 1984, with 95% confidence intervals between 1 in 1,692 to 1 in 2,336.
Macek et al. (1997) reported a large-scale study for mutation identification in African American CF patients. The entire coding and flanking intronic sequence of the CFTR gene was analyzed by denaturing gradient-gel electrophoresis (DGGE) and sequencing in 82 African American CF chromosomes. One novel mutation, 3120+1G-A (602421.0120), occurred with a frequency of 12.3% and was also detected in a native African patient. To establish gene frequencies, an additional group of 66 African American CF chromosomes were screened for mutations identified in 2 or more African American patients. Screening for 16 'common Caucasian' mutations identified 52% of CF alleles in African Americans, while screening for 8 'common African' mutations accounted for an additional 23%. The combined detection rate of 75% was comparable to the sensitivity of mutation analysis in Caucasian CF patients. These results indicated that African Americans have their own set of 'common' CF mutations that originated from the native African population.
To examine whether the 3120+1G-A mutation has a common origin in the diverse populations in which it has been observed or whether its widespread distribution is the result of recurrent mutational events, Dork et al. (1998) analyzed DNA samples obtained from 17 unrelated CF patients in 4 different populations and from 8 unrelated African CF carriers. They found identical extended CFTR haplotypes for the 3120+1G-A alleles in Arab, African, and African American patients, strongly suggesting that the mutation had a common origin. This finding was not surprising in the case of Africans and African Americans; it was not as easy to explain the presence of the 3120+1G-A mutation in African and Saudi Arab patients. Recent ethnic admixture accounts for a few percent of Africans in Saudi Arabia; however, this was considered an unlikely explanation of the finding, since none of the Saudi families with the mutation had any anthropomorphologic signs of an African descent. In the past, a continuous gene flow between Arab and African populations probably persisted for many centuries, in association with trading and with the spread of the Islamic religion. Thus far, the Greeks are the only Caucasian population in which the 3120+1G-A mutation has been identified. A recurrent mutational event seems to be unlikely, because the Greek haplotype differs from the others in only minor respects. Historical contacts, e.g., under Alexander the Great or during the ancient Minoan civilization, may provide an explanation for the common ancestry of the disease mutation in these ethnically diverse populations. Dork et al. (1998) concluded that 3120+1G-A is an ancient mutation that may be more common than previously thought in populations of the tropical and subtropical belt, where CF probably is an underdiagnosed disorder.
Padoa et al. (1999) screened 1,152 unrelated, healthy African blacks from southern, western, and central Africa, and 9 black CF patients for the 3120+1G-A mutation. The mutation was found to have a carrier frequency of 1 in 91 for South African blacks, with a 95% confidence interval of 1 in 46 to 1 in 197. A subset of those studied were also screened for the A559T, S1255X, and 444delA mutations. These mutations were not found in any of the patients or in over 373 healthy subjects tested. Padoa et al. (1999) concluded that the corrected CF carrier frequency in South African blacks would be between 1 in 14 and 1 in 59 and, hence, that the incidence of CF would be predicted to be between 1 in 784 and 1 in 13,924 in this population. Padoa et al. (1999) speculated as to why the observed incidence in this population is lower than that which they predicted.
Restrepo et al. (2000) used a reverse dot-blot detection kit to examine the frequency of 16 CFTR mutations among 192 cystic fibrosis alleles in Mexico, Colombia, and Venezuela. The detection efficacy of the panel used was 47.9% in this population. The most prevalent CF allele was delF508 (39.6%). The most common alleles among the others were G542X, N1303K and 3849+10kbC-T (602421.0062). The authors compared their results to population studies from Spain and concluded that an important Spanish contribution is present in CFTR mutations in these 3 countries, but that important regional differences in allele prevalence exist.
Kabra et al. (2000) analyzed CFTR mutations in 24 children with CF from the Indian subcontinent. Of the mutant chromosomes, 33.3% had the delF508 mutation. The authors screened 16 exons of the CFTR gene by SSCP and heteroduplex analysis, but mutations were not identified in 46% of chromosomes. The authors also reported novel mutations in their population: 3622insT (602421.0125) and 3601-20T-C (602421.0126).
Wang et al. (2000) found that 7 of 29 Hispanic patients with CF were heterozygous for a single-basepair deletion at nucleotide 3876 resulting in a frameshift and termination at residue 1258 of the CFTR gene (602421.0127). This mutation therefore accounted for 10.3% of mutant alleles in this group. The patients with this mutation had a severe phenotype as determined by age of diagnosis, high sweat chloride, presence of allergic bronchopulmonary aspergillosis, pancreatic insufficiency, liver disease, cor pulmonale, and early death. Wang et al. (2000) also noted that this mutation had not been reported in any other ethnic group.
Considering that the haplotype background of the mutations that most often cause cystic fibrosis in Europe is different from that of non-CF chromosomes, Mateu et al. (2002) reasoned that these haplotype backgrounds might be found at high frequencies in populations in which CF was currently not common; thus, such populations would be candidates for the place of origin of CF mutations. In a worldwide survey of normal chromosomes, they found a very low frequency or absence of the most common CF haplotypes in all populations analyzed, and a strong genetic variability and divergence, among various populations, of the chromosomes that carry disease-causing mutations. They suggested that the depth of the gene genealogy associated with disease-causing mutations may be greater than that of the evolutionary process that gave rise to the current human populations. The concept of 'population of origin' lacks either spatial or temporal meaning for mutations that are likely to have been present in Europeans before the ethnogenesis of the current populations. Subsequent population processes may have erased the traces of their geographic origin.
In Brittany, France, Scotet et al. (2003) reviewed the results of a neonatal screening program for CF begun in 1989 to determine the prevalence of CF at birth and to review data from prenatal diagnoses carried out in the region, first in families related to a CF child and also those made following the detection of an echogenic bowel upon routine ultrasound examination performed during pregnancy. The prevalence of CF at birth was estimated to be 1 in 2,838 in the region from 1992 to 2001. By including the 54 CF-affected pregnancies that were terminated during those 10 years, the corrected birth prevalence of CF was 1 in 1,972. Prenatal diagnosis was therefore responsible for a decrease in CF prevalence at birth of 30.5%.
Quint et al. (2005) described the mutation spectrum in Jewish CF patients living in Israel. Using a panel of 12 CFTR mutations, they identified 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jews of North African origin, and 75% in Jewish patients from Iraq.
In a survey of 495 blood samples of randomly selected healthy individuals in Hanoi, Vietnam, Nam et al. (2005) found no instance of the delta-F508 mutation.
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 (rs113993960; 602421.0001), 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. They identified the met1101-to-lys mutation (602421.0137) in 108 heterozygotes and 6 homozygotes among 1,473 screened, for a carrier frequency of 0.073 (1 in 13.5).
Among 23,369 ethnically diverse individuals screened for cystic fibrosis carrier status, Lazarin et al. (2013) identified 842 carriers (3.6%), for an estimated carrier frequency of approximately 1 in 28. Twenty-seven 'carrier couples' were identified. Nine individuals were identified as homozygotes or compound heterozygotes. Among 12,870 individuals of northwestern European origin, the carrier frequency was 1 in 23. A carrier frequency of 1 in 40 was found among 1,122 south Asians screened, supporting reports that cystic fibrosis is underreported in this population.
Feuchtbaum et al. (2012) reported the birth rates of selected metabolic, endocrine, hemoglobin, and cystic fibrosis disorders for specific racial/ethnic groups in a total of 2,282,138 newborns born between 2005 and 2010 in California who were screened using a blood sample collected via heel stick. Feuchtbaum et al. (2012) found an overall birth prevalence for confirmed cystic fibrosis of approximately 20 per 100,000 births. Screening of 14,872 Native American individuals gave an estimated birth prevalence of approximately 37 per 100,000 births. Screening of 561,910 white individuals gave an estimated birth prevalence of approximately 39 per 100,000 births. Screening of 118,992 black individuals gave an estimated birth prevalence of approximately 17 per 100,000 births.
Hansson (1988) speculated that if the defect in the control of apical membrane chloride ion channels in CF extends to the intestine, a resistance to bacterial toxin-mediated diarrhea might confer a selective advantage on carriers for the CF gene. Baxter et al. (1988) presented actual observations indicating that intestine in CF homozygotes fails to exhibit a secretory response on exposure to bacterial toxins that would normally induce a secretory diarrhea. They were proceeding to investigate intestinal secretory responses of heterozygotes. The high frequency of the CF gene might be explained by this mechanism. Romeo et al. (1989) also suggested that a selective advantage consisting of high resistance to chloride-ion-secreting diarrheas might have favored, in the past, survival of infants heterozygous for the CF gene.
McMillan et al. (1989) demonstrated an apparent association between heterozygosity at the cystic fibrosis locus and heterozygosity for a RFLP near the constant region of the T-cell receptor beta chain (186930). They suggested that this previously unreported disease association might indicate some form of epistatic interaction between the CF gene and the TCRB gene such that the double heterozygote is immunologically advantaged.
Rodman and Zamudio (1991) suggested that resistance to cholera may have been the environmental factor that selected CF heterozygotes over their 'normal' homozygote cohort. This suggestion obtained experimental support from the observations of Gabriel et al. (1994). In a study of the CFTR -/- mouse, created by disruption by the CFTR gene at exon 10 by insertion of an in-frame stop codon to replace ser489, they found that transgenic mice that expressed no CFTR protein did not secrete fluid in response to cholera toxin. Heterozygotes expressed 50% of the normal amount of CFTR protein in the intestinal epithelium and secreted 50% of the normal fluid and chloride ion in response to cholera toxin. The findings suggested that CF heterozygotes may possess a selective advantage of resistance to cholera.
Pier et al. (1998) investigated whether increased resistance to typhoid fever in the heterozygote could be a factor in maintaining mutant CFTR alleles at high levels in selected populations. Typhoid fever 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, delF508 (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 delF508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than did wildtype Cftr mice; no translocation occurred in delF508 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 delF508 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.
Hogenauer et al. (2000) used an intestinal perfusion technique to measure in vivo basal and prostaglandin-stimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF. Patients with CF had essentially no active chloride secretion in the basal state, and secretion was not stimulated by a prostaglandin analog. However, CF heterozygotes secreted chloride at the same rate as did people without a CF mutation. If heterozygotes are assumed to have less than normal intestinal CFTR function, these results mean that CFTR expression is not rate limiting for active chloride secretion in heterozygotes. The results did not support the theory that the very high frequency of CF mutations is due to a survival advantage that is conferred on heterozygotes who contract diarrheal diseases mediated by intestinal hypersecretion of chloride, such as infection with Vibrio cholerae or E. coli.
Mouse Model
Because the pulmonary complications of CF are the most morbid aspects of the disease, a potential therapeutic strategy is to reconstitute expression of the normal CFTR gene in airway epithelia by somatic gene transfer. Engelhardt et al. (1992) developed an animal model of the human airway, using bronchial xenografts engrafted on rat tracheas and implanted into nude mice, and tested the efficiency of in vivo retroviral gene transfer. They found that in undifferentiated regenerating epithelium, 5 to 10% retroviral gene transfer was obtained, whereas in fully differentiated epithelium, no gene transfer was noted. These findings suggested that retroviral-mediated gene transfer to the airways in vivo may be feasible if the proper regenerative state can be induced.
Several groups succeeded in constructing a transgenic mouse model of cystic fibrosis (Clarke et al., 1992; Colledge et al., 1992; Dorin et al., 1992; Snouwaert et al., 1992). Unlike the HPRT-deficient mouse, constructed as a model for the Lesch-Nyhan syndrome (308000), the CFTR-deficient homozygote showed measurable defects in ion permeability of airway and intestinal epithelia, similar to those demonstrable in human CF tissues. Furthermore, most of the deficient mice had intestinal pathology similar to that of meconium ileus. Also, there appeared to be no prenatal loss from litters produced from crosses between heterozygotes. Most of the mice, however, died soon after birth as a consequence of intestinal blockage. Unlike the human male, the homozygous mouse male in at least one instance was fertile. In a transgenic mouse model of CF created by Dorin et al. (1994) through insertion in exon 10, only a low incidence of meconium ileus was observed. In contrast to the very high level of fatal intestinal obstruction in 3 other CF mouse models, they showed that the partial duplication consequent upon insertional gene targeting allowed exon skipping and aberrant splicing to produce normal Cftr mRNA, but at levels greatly reduced compared with wildtype mice. Instead of the predicted mutant Cftr transcript, a novel mRNA was produced that utilized cryptic splice sites in the disrupting plasmid sequence. Although residual wildtype mRNA in the exon 10 insertional mutant mouse seems to ameliorate the severity of the intestinal phenotype observed in the absolute 'null' CF mice, the presence of low-level residual wildtype Cftr mRNA does not correct the CF ion transport defect. The long-term survival of this insertional mutant mouse provides the opportunity to address factors important in the development of lung disease. To correct the lethal intestinal abnormalities that occur in the transgenic CFTR-null mouse, Zhou et al. (1994) used the human CFTR gene under the control of the rat intestinal fatty acid binding protein (134640) gene promoter. The mice survived and showed functional correction of ileal goblet cell and crypt cell hyperplasia and cAMP-stimulated chloride secretion. The results supported the concept that transfer of the human CFTR gene may be a useful strategy for correcting physiologic defects in patients with CF.
Mice homozygous for disruption of the Cftr gene, unlike the human disease, fail to show any gross lung pathology (Rozmahel et al. (1996)). It was proposed that a calcium-activated Cl(-) conductance could compensate for the lack of the Cftr-encoded Cl(-) channel function in these mice. The absence of this alternative chloride transport mechanism in the intestinal epithelial cells was believed to be responsible for the severe intestinal pathology observed in the same mice. Prolonged survival in these mice was demonstrated among backcross and intercross progeny with different inbred strains, suggesting that modulation of disease severity was genetically determined. A genome scan showed that the major modifier locus mapped near the centromere of mouse chromosome 7 in a region of conserved synteny with human chromosome 19q13. Candidate genes in that region include the gamma-subunit of protein kinase C (176980), the alpha-3 subunit of the type 1 Na(+)/K(+) exchanging ATPase (182350), and the sodium channel, type 1, beta-polypeptide (600235).
Kent et al. (1997) described the phenotype of an inbred congenic strain of CFTR-knockout mouse that developed spontaneous and progressive lung disease of early onset. The major features of the lung disease included failure of effective mucociliary transport, postbronchiolar overinflation of alveoli, and parenchymal interstitial thickening, with evidence of fibrosis and inflammatory cell recruitment. Kent et al. (1997) speculated that the basis for development of lung disease in the congenic CFTR-knockout mice is their observed lack of a non-CFTR chloride channel normally found in CFTR-knockout mice of mixed genetic background.
Using an intact human CFTR gene, Manson et al. (1997) generated transgenic mice carrying a 320-kb YAC. Mice that only expressed the human transgene were obtained by breeding with Cambridge-null CF mice. One line had approximately 2 copies of the intact YAC. Mice carrying this transgene and expressing no CFTR appeared normal and bred well, in marked contrast to the null mice, where 50% died by approximately 5 days of age. The chloride secretory responses in mice carrying the transgene were as large as or larger than those in the wildtype tissues. Expression of the transgene was highly cell-type specific and matched that of the endogenous mouse gene in the crypt epithelia throughout the gut and in salivary gland tissue. However, there was no transgene expression in some tissues, such as the Brunner glands, where it would be expected. Where there were differences between the mouse and human pattern of expression, the transgene followed the mouse pattern.
Coleman et al. (2003) found that under proper conditions, transgenic CF mice are hypersusceptible to P. aeruginosa colonization and infection and can be used for evaluation of lung pathophysiology, bacterial virulence, and development of therapies for CF lung disease.
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. 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. Thus, 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.
To test the hypothesis that accelerated sodium transport can produce cystic fibrosis-like lung disease, Mall et al. (2004) generated mice with airway-specific overexpression of epithelial sodium channels. Mall et al. (2004) used the airway-specific club cell secretory protein promoter to target expression of individual SCNN1 subunit (see 600760) transgenes to lower airway epithelia. They demonstrated that increased airway sodium absorption in vivo caused airway surface liquid volume depletion, increased mucus concentration, delayed mucus transport, and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation, and poor bacterial clearance. Mall et al. (2004) concluded that increasing airway sodium absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.
Harmon et al. (2010) found that colonic epithelial cells and whole lung tissue from Cftr-null mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma; 601487) function that contributes to a pathologic program of gene expression. Lipidomic analysis of colonic epithelial cells suggested that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E2. Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalized the altered gene expression pattern associated with Cftr deficiency and reduced disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrase IV (CA4; 114750) and carbonic anhydrase II (CA2; 611492), increases bicarbonate secretion, and reduces mucous retention. Harmon et al. (2010) concluded that their studies revealed a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.
Ovine Model
In connection with the design of a large-animal model for cystic fibrosis, Tebbutt et al. (1995) cloned and sequenced the CFTR cDNA of sheep. It showed a high degree of conservation at the DNA coding and predicted polypeptide levels with human CFTR; at the nucleotide level, there was a 90% conservation (compared with 80% between human and mouse). At the polypeptide level, the degree of similarity was 95% (compared with 88% between human and mouse). Northern blot analysis and reverse transcription-PCR showed that the patterns of expression of the ovine CFTR gene are very similar to those seen in humans. Further, the developmental expression of CFTR in the sheep is equivalent to that observed in humans.
Harris (1997) pointed out that the generation of cloned sheep (Campbell et al., 1996; Wilmut et al., 1997) establishes the practicality of creating an ovine model of CF. The failure of mice with disruption of the Cftr gene to reproduce the pulmonary and pancreatic features of CF may be due, in the case of the lung at least, in part to considerable differences in submucosal gland distribution in mouse and human. Mice have very few of these glands and they are restricted to the tracheal submucosa. The CFTR chloride ion channel is not expressed at high levels in the mouse pancreas, in contrast to humans where the pancreas is the site of most abundant CFTR expression. Sheep and human CFTR show greater identity and similarity than do human and mouse. Furthermore, Harris (1997) noted that the tissue-specific pattern of expression of the ovine CFTR gene and the developmental expression of CFTR in the sheep are very similar to that in humans. CF pathology commences in utero; for example, obstruction of CF pancreatic ducts by deposits of secreted material commences in the midtrimester of human gestation and by term the pancreas is structurally and functionally destroyed. Thus, in utero therapy might be necessary.
Porcine Model
Rogers et al. (2008) generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The lungs of newborn CFTR-null piglets appeared normal.
Chen et al. (2010) reviewed features of the pig model of CF, which closely resembles the human disease. At birth, Cftr -/- pigs manifest pancreatic destruction, meconium ileus, early focal biliary cirrhosis, and microgallbladder. Within hours of birth, Cftr -/- pigs show reduced ability to eliminate bacteria from the lungs, but no inflammation. The inability to eliminate bacteria results in spontaneous lung disease within a few months of birth, including inflammation, infection, mucous accumulation, tissue remodeling, and airway obstruction. Chen et al. (2010) studied ion transport in newborn Cftr -/- pig nasal and tracheal/bronchial epithelia in tissues and cultures and in vivo, prior to the onset of airway inflammation. Cftr -/- epithelia showed markedly reduced Cl- and HCO3- transport, but there was no increase in transepithelial Na+ or liquid absorption or reduction in periciliary liquid depth. Like human CF, Cftr -/- pigs showed increased amiloride-sensitive voltage and current, but this was due to lack of Cl- conductance rather than increased Na+ transport.
To assess whether impaired mucociliary transport (MCT) is a primary deficit in CF or is secondary to airway remodeling, Hoegger et al. (2014) tracked movement of radiodense microdisks in airways of newborn piglets with cystic fibrosis. Cholinergic stimulation, which elicits mucus secretion, substantially reduced microdisk movement. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. Thus, Hoegger et al. (2014) concluded that impaired MCT is a primary defect in cystic fibrosis, suggesting that submucosal glands and tethered mucus may be targets for early CF treatment.
Atresia of the ileum was reported by Blanck et al. (1965) in 2 brothers with cystic fibrosis; 2 other sibs had cystic fibrosis without intestinal atresia.
Spock et al. (1967) observed that patients have a factor in serum that inhibits the action of cilia in explants of rabbit tracheal mucosa. Serum from heterozygotes contained an amount of the factor intermediate between none (the normal situation) and the level in patients.
Smith et al. (1968) found cystic fibrosis in a child with cri-du-chat syndrome (123450). Only the mother was heterozygous by Spock test. They suggested that loss of part of the short arm of the chromosome 5 derived from the father had occurred and that the deleted portion carried the cystic fibrosis locus. Danes and Bearn (1968) found vesicular metachromasia in the fibroblasts of both parents suggesting that the reported experience cannot be taken as evidence of localization of the CF gene on the short arm of chromosome 5.
Vitale et al. (1986) found close linkage of the CF gene and the MET locus in 12 unrelated Italian cystic fibrosis families, thus supporting their hypothesis of genetic homogeneity based on the analysis of consanguineous marriages among 624 couples of CF parents. Lander and Botstein (1986) and Romeo et al. (1986) discussed further the consanguinity method for studying heterogeneity in cystic fibrosis. Estivill et al. (1987) used their haplotype data to argue against genetic heterogeneity at the CF locus. They proposed that the great majority of CF mutations found in the population arose from an original mutational event which occurred in the Caucasian population after racial divergence in man.
Edwards et al. (1984) reported a family in which deficiency at the tip of 13q was associated with cystic fibrosis. Weak evidence supporting assignment to 13q was provided by a boy with both cystic fibrosis and hemophilia A; no translocation was visualized but the authors postulated a telomeric translocation that disrupted both loci at the tip of the X chromosome and chromosome 13. They cited 2 other observations of cystic fibrosis with chromosome 13 abnormality.
Williamson (1984) excluded cystic fibrosis from chromosome 13; none of the DNA probes that were monosomic in the case of Edwards et al. (1984) were linked to cystic fibrosis in studies of affected sibs.
In skin fibroblasts from both homozygotes and heterozygotes, Danes and Bearn (1968) found cytoplasmic intravesicular metachromasia of a type readily distinguished from that of mucopolysaccharidoses. Danes and Bearn (1969) described a morphologic change in the fibroblasts and furthermore suggested that homozygosity at either of two different loci can produce cystic fibrosis. In type I, the fibroblasts show discrete metachromatic cytoplasmic vesicles and normal mucopolysaccharide content. In type II, fibroblast metachromasia is present in both vesicles and granules and is evenly distributed through the cytoplasm; mucopolysaccharide content of the cells is markedly increased. On the basis of cell culture phenotype, Danes et al. (1978) identified 3 classes of cystic fibrosis and concluded that there is a prognostic difference between classes. They also suggested that their Class III represents the genetic compound. A deficiency of arginine esterase has been suggested by Rao and Nadler (1974), who reported absence of 1 of 3 isozymes in various cases of cystic fibrosis. Their hypothesis is that the ciliary factor and related substances are present because of failure of degradation when the enzyme is deficient. Stern et al. (1978) described a cystic fibrosis variant with little pancreatic abnormality. Hosli and Vogt (1979) claimed the successful discrimination of cystic fibrosis patients, obligatory heterozygotes (parents), and normal controls by heat inactivation of acid phosphatase and alpha-mannosidase in plasma. In this test, normals retain 80 to 100% activity, heterozygotes 40 to 60%, and CF patients almost none. There was no overlap between groups. Katznelson et al. (1983) did a stringently blinded trial of the reliability of the test of Hosli and Vogt (1979), submitting doubly coded samples to Dr. Hosli. The genotype was correctly identified in each of 45 cases. Shapiro and Lam (1982) found that the usual increase in intracellular calcium in fibroblasts with successive time (passages) in culture is exaggerated in cystic fibrosis fibroblasts. In kidney specimens obtained at autopsy from patients with cystic fibrosis, Katz et al. (1988) documented microscopic nephrocalcinosis in 35 of 38 specimens. Hypercalciuria was present in 5 of 14 patients studied. The presence of microscopic nephrocalcinosis in 3 patients less than 1 year of age suggested to these authors that the mutation in cystic fibrosis involves a primary abnormality of renal calcium metabolism. Shapiro et al. (1982) reported anomalous kinetics of mitochondrial NADH dehydrogenase in cystic fibrosis homozygotes and heterozygotes. Studying white cells, Sanguinetti-Briceno and Brock (1982) could not identify a correlation between NADH dehydrogenase and CF genotype. Shepherd et al. (1988) found that cystic fibrosis infants had 25% higher rates of total energy expenditure compared to healthy infants matched for age and body weight. The authors suggested that the data point to an energy-requiring basic defect.
Cleghorn et al. (1986) obtained good results from oral administration of a balanced solution rendered nonabsorbable by addition of polyethylene glycol.
In a multicenter, randomized, controlled, crossover trial of prepubertal children with cystic fibrosis, Hardin et al. (2006) found that treatment with recombinant human growth hormone (rhGH) improved height and weight, decreased the number of hospitalizations, and improved quality of life in 32 children who received the treatment compared to 29 children not treated. These effects were sustained after rhGH was discontinued.
Reviews
Collins (1992) gave an update concerning the molecular biology of CF and the therapeutic implications thereof.
Boucher (1999) reviewed the status of gene therapy for CF lung disease.
O'Sullivan and Freedman (2009) reviewed the clinical features, pathogenesis, diagnosis, molecular genetics, and current state of gene therapy in CF.
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