Alternative titles; symbols
HGNC Approved Gene Symbol: GJA1
SNOMEDCT: 31291009, 38215007, 715725001, 719518004;
Cytogenetic location: 6q22.31 Genomic coordinates (GRCh38): 6:121,435,646-121,449,727 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q22.31 | Craniometaphyseal dysplasia, autosomal recessive | 218400 | Autosomal recessive | 3 |
| Erythrokeratodermia variabilis et progressiva 3 | 617525 | Autosomal dominant | 3 | |
| Oculodentodigital dysplasia | 164200 | Autosomal dominant | 3 | |
| Oculodentodigital dysplasia, autosomal recessive | 257850 | Autosomal recessive | 3 | |
| Palmoplantar keratoderma with congenital alopecia | 104100 | Autosomal dominant | 3 | |
| Syndactyly, type III | 186100 | Autosomal dominant | 3 |
The GJA1 gene encodes connexin-43 (Cx43), one of the most abundant connexin proteins. Cxs are a family of transmembrane proteins with molecular masses varying from 26 to 60 kD; Cx43 has a molecular mass of 43 kD. In vertebrates, Cxs are the building blocks of gap junction channels, intercellular channels that connect the cytoplasm of 2 neighboring cells. A GJ channel consists of 2 hemichannels, each composed of 6 Cx proteins and delivered by each of the coupled cells. Cx43 is ubiquitously present in the human body in many tissues and cells (summary by De Bock et al., 2013).
Two members of the connexin gene family, connexins 43 and 32 (GJB1; 304040), are abundantly expressed in the heart and liver, respectively. Li et al. (1995) demonstrated that GAP43-like immunoreactivity in rat is mainly present in sympathetic and sensory nerve fibers as well as in perivascular nerve terminals. This peptide is axonally transported predominantly in sensory and adrenergic axons.
By immunofluorescence and phase-contrast microscopy, Lee et al. (1992) detected similar labeling of normal mammary epithelial cells when probed for CX43 and CX26. Both connexins showed diffuse intracellular staining and a punctate distribution that often corresponded to regions of cell-cell contact. Mammary tumor epithelial cells did not express either connexin.
Kaba et al. (2001) noted that cardiac myocytes are electrically coupled via gap junctions. Immunohistochemical staining of embryonic mouse and human fetal hearts localized CX43 in the trabeculated layer of developing ventricles, with stronger staining on the right side. In the adult human ventricle, CX43 was expressed at the epicardial aspect.
By immunohistochemistry and Western blot analysis, Arishima et al. (2002) detected CX26 and CX43 in the cap cell layer, cap cell cluster, and central core of arachnoid villi. Expression was weaker in the fibrous capsule. In meningiomas, the connexins were strongly expressed in the meningotheliomatous area and were weakly expressed in the fibrous area. Neither was expressed in hemangiopericytomas. CX26 and CX43 were distributed on the cell membranes in arachnoid villi and meningiomas and showed apparent molecular masses of 26 kD and 42 to 47 kD, respectively.
Sohl et al. (2003) stated that the mouse and human CX43 share 97% amino acid identity. Northern blot analysis detected variable expression of a 3.0-kb CX43 transcript in both mouse and human, with highest expression in heart.
Using a rat cDNA probe in Southern analysis of a panel of human-mouse somatic cell hybrids, Willecke et al. (1990) assigned the CX43 gene (also symbolized GJA1) to 6q14-qter. A pseudogene of connexin-43, which lacks an intron, was located on human chromosome 5. Through analysis of somatic cell hybrids by PCR and hybridization, Fishman et al. (1991) mapped the gene for heart connexin-43 (GJA1) to chromosome 6. A pseudogene, symbolized GJA1P, was assigned to chromosome 5. The structures of GJA1 and the liver connexin gene, GJB1, are sufficiently similar to suggest that they arose from a single progenitor. By study of somatic cell hybrids, Hsieh et al. (1991) mapped the GJA1 gene to 6p21.1-q24.1. Corcos et al. (1993) narrowed the assignment to 6q21-q23.2 by study of a human/rodent somatic cell hybrid mapping panel.
By study of rat/mouse somatic cell hybrids, Hsieh et al. (1991) assigned the corresponding gene in mouse to chromosome 10.
To identify the molecular basis for the function of connexin-43, Fishman et al. (1991) used site-directed mutagenesis to generate mutant cDNAs of human connexin-43 with shortened cytoplasmic tail domains. Results suggested that the cytoplasmic tail domain is an important determinant of the unitary conductance event of gap junction channels but not their voltage dependence.
Using dye transfer to detect the presence of functional gap junctions, Lee et al. (1992) determined that normal mammary epithelial cells that expressed CX26 (121011) and CX43, but not tumor cells that did not express them, contained functional gap junctions. In synchronized cells, CX26 expression was regulated by the cell cycle, showing moderate expression during G1 and S and strong upregulation in late S and G2. CX43 was constitutively expressed at a uniform low level throughout the cell cycle. Phorbol ester induced reexpression of the 2 CX26 transcripts in mammary tumor epithelial cells, but not reexpression of CX43.
The migration of lymphocytes from the circulation into tissues involves a number of adhesion molecules and the expression of new molecules. Gap junctions facilitate cell-to-cell adhesion and provide pathways for direct intercellular communication. Oviedo-Orta et al. (2000) noted that GJA1 is expressed in a number of lymphoid organs. By RT-PCR, Western blot, and flow cytometric analyses, they showed that lymphocytes express GJA1 and GJA5 (121013), but not GJB2 (121011), GJB1 (304040), GJA4 (121012), or GJA7 (608655); GJA5 expression was restricted to tonsillar T and B lymphocytes. Flow cytometric analysis showed that GJA1 and GJA5 expression increases after mitogenic stimulation. Extracellular connexin mimetic peptide blocked dye transfer between lymphocyte subpopulations, and gap junction inhibitors decreased the production of IgM in cocultured T and B lymphocytes. The results identified gap junction proteins as important cell surface components that modulate immune responses.
Tsai et al. (2003) noted that expression of CX43, CX45 (GJA7), and CX37 (GJA4) had been shown to reflect the stage and maturity of luteinized follicles in animal studies. They found that these connexins were expressed in most of the granulosa cells from human luteinized preovulatory follicles. Expression abruptly decreased in stimulated follicles larger than 5.5 mL. Only expression of CX43 predicted better prognosis for in vitro fertilization.
Burdine and Schier (2000) reviewed convergent and divergent mechanisms in left-right axis formation in chick, mouse, frog, and zebrafish and the role of mutations in EBAF (601877), ACVR2B (602730), ZIC3 (300265), and connexin-43 in humans.
Neijssen et al. (2005) demonstrated that peptides with a molecular mass of up to approximately 1,800 diffuse intercellularly through gap junctions unless a 3-dimensional structure is imposed. This intercellular peptide transfer causes cytotoxic T cell recognition of adjacent, innocent bystander cells as well as activated monocytes. Gap junction-mediated peptide transfer is restricted to a few coupling cells owing to the high cytosolic peptidase activity. Neijssen et al. (2005) presented a mechanism of antigen acquisition for crosspresentation that couples the antigen presentation system of 2 adjacent cells and is lost in most tumors: gap junction-mediated intercellular peptide coupling for presentation by bystander MHC class I molecules and transfer to professional antigen-presenting cells for crosspriming.
Using coimmunoprecipitation experiments, Akiyama et al. (2005) showed that CIP150 (610354) interacted with GJA1. GJA1 deletion constructs were used to map the CIP150-GJA1 interaction domain to amino acids 227 to 242 of GJA1. This interaction domain of GJA1 was also necessary for phosphorylation, localization to cell-cell contacts, and dye transfer activity of GJA1. When expression of CIP150 was suppressed using RNA interference, GJA1 did not localize to gap junction plaques and gap junction dye transfer activity was significantly reduced.
Using a photolytic uncaging approach to induce focal increases in Ca(2+) levels in targeted endothelial cells of rat lung alveolar capillaries, Parthasarathi et al. (2006) observed that Ca(2+) levels increased in vascular locations up to 150 micrometers from the target site, indicating that Ca(2+) was conducted from the capillary to adjacent vessels. No such conduction was evident in Cx43 -/- mouse lungs or in rat lungs pretreated with peptide inhibitors of Cx43, providing evidence that interendothelial Ca(2+) conduction in the lung capillary bed is mediated by CX43-containing gap junctions. Increases in Ca(2+) levels in capillaries caused a proinflammatory activation of the leukocyte adherence receptor P-selectin (SELP; 173610) in venules; peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases. Parthasarathi et al. (2006) concluded that CX43-mediated gap junctions serve as conduits for the spread of proinflammatory signals in the lung capillary bed.
Elias et al. (2007) showed that the gap junction subunits CX26 and CX43 are expressed at the contact points between radial fibers and migrating neurons, and that acute downregulation of CX26 or CX43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibers as well as the subsequent translocation of the nucleus. Elias et al. (2007) concluded that gap junction adhesions are necessary for glial-guided neuronal migration.
Oxford et al. (2007) used RNA silencing to decrease the expression of plakophilin-2 (PKP2; 602861) in neonatal rat cardiomyocytes and epicardial cells and found that loss of PKP2 expression led to a decrease in total CX43 expression, a significant redistribution of CX43 to the intracellular space, and a decrease in dye coupling between cells. Separate experiments indicated that PKP2 and CX43 are part of a common macromolecular complex; together, the results supported the notion of molecular crosstalk mediating gap junction remodeling subsequent to disruption of the desmosome.
Roell et al. (2007) showed that the transplantation of embryonic cardiomyocytes in myocardial infarcts protects against the induction of ventricular tachycardia in mice. Engraftment of embryonic cardiomyocytes, but not skeletal myoblasts, bone marrow cells, or cardiac myofibroblasts, markedly decreased the incidence of ventricular tachyarrhythmias induced by in vivo pacing. Embryonic cardiomyocote engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and calcium ion signals from engrafted embryonic cardiomyocytes expressing a genetically encoded calcium ion indicator could be entrained during sinoatrial cardiac activation in vivo. Embryonic cardiomyocyte grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. Ventricular tachycardia protection is critically dependent on expression of the gap junction protein connexin-43: skeletal myoblasts genetically engineered to express Cx43 conferred a similar protection to that of embryonic cardiomyocytes against induced ventricular tachycardia. Thus, Roell et al. (2007) concluded that engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy.
Using real-time alveolar imaging in situ, Westphalen et al. (2014) showed that a subset of alveolar macrophages that are attached to the alveolar wall form CX43-containing gap junction channels with the epithelium. During lipopolysaccharide (LPS)-induced inflammation, the alveolar macrophages remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca(2+) waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca(2+)-dependent activation of AKT (see 164730), since alveolar macrophage-specific knockout of CX43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. Westphalen et al. (2014) concluded that their results suggested a novel immunomodulatory process in which a subset of alveolus-attached macrophages intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.
Oculodentodigital Dysplasia
Oculodentodigital dysplasia (ODDD; 164200) is an autosomal dominant disorder with high penetrance, intra- and interfamilial phenotypic variability, and advanced paternal age in sporadic cases. The syndrome presents with craniofacial (ocular, nasal, and dental) and limb dysmorphisms, spastic paraplegia, and neurodegeneration. Syndactyly type III (186100) and conductive deafness occur in some cases, and cardiac abnormalities are infrequent. Paznekas et al. (2003) studied 17 families with oculodentodigital dysplasia and found mutations in the GJA1 gene in all affected members. Sixteen different missense mutations and 1 codon duplication were detected (see, e.g., 121014.0003-121014.0007). These mutations may cause misassembly of channels or alter channel conduction properties. The mutation analysis supported clinical observations that ODDD is fully penetrant, since all carriers of mutations exhibited craniofacial and limb dysmorphisms. Intrafamilial variability of the major phenotypic characteristics was observed for all mutations segregating in multiplex families. Expression patterns and phenotypic features of Gja1 mutant animals, reported by others, were considered compatible with the pleiotropic clinical presentation of oculodentodigital dysplasia.
Richardson et al. (2006) identified homozygosity for a nonsense mutation in the GJA1 gene (121014.0016) in 2 sisters with an autosomal recessive form of ODDD (257850).
Paznekas et al. (2009) reported 18 new GJA1 mutations in 28 ODDD patients, and reviewed the 62 known mutations in GJA1 as well as the phenotypic information available on 177 affected individuals from 54 genotyped families. The authors noted that CX43 alterations had been found in each of the defined protein domains, and that most (85%) occurred in the first half of the protein, prior to amino acid 192. The majority (85%) of mutations were dominant missense mutations resulting in ODDD; 8 were recurrent mutations, with no more than 5 cases for each, and there were 10 amino acid codons at which 2 or 3 different mutations have been found. Paznekas et al. (2009) noted that phenotypic variability occurred even among family members with the same mutation, and stated that making genotype/phenotype correlations was difficult, since there were no predominant mutations and mutations were equitably distributed throughout most protein domains.
In 4 affected members of a family with ODDD and lymphedema, Brice et al. (2013) identified heterozygosity for a missense mutation in the GJA1 gene (K206R; 121014.0022). The mutation was not found in an unaffected family member or in 600 controls. Brice et al. (2013) noted that mutation in a related gene, GJC2 (608803), had been associated with 4-limb edema (613480) with a similar pattern on lymphoscintigraphy.
Syndactyly Type III
Richardson et al. (2004) described 10 mutations in the GJA1 gene, 7 of which were novel, bringing to 24 the number of GJA1 mutations reported. All but 1 of these mutations resulted in the introduction of a missense change into the N-terminal two-thirds of connexin-43, highlighting the functional importance of this region of the protein. One of these mutations, gly143 to ser (G143S; 121014.0008), occurred in a family that exhibited type III syndactyly but not the ophthalmic, skeletal, or dental findings usually associated with ODDD.
In 2 patients with typical features of ODDD and the additional features of optic nerve and retinal dysplasia in both and ciliary body cysts in 1, Gabriel et al. (2011) identified heterozygous mutations in the GJA1 gene (121014.0019-121014.0020).
Craniometaphyseal Dysplasia, Autosomal Recessive
In affected members of 3 unrelated consanguineous families with autosomal recessive craniometaphyseal dysplasia (CMDR; 218400) as well as in a sporadic CMD patient, Hu et al. (2013) identified homozygosity for a missense mutation in the GJA1 gene (121014.0021). The mutation segregated with disease in each family and was not found in the dbSNP, HGMD, 1000 Genomes Project, or NHLBI Exome Sequencing Project databases.
Palmoplantar Keratoderma and Congenital Alopecia 1
In 3 patients from 2 Chinese families with palmoplantar keratoderma and congenital alopecia-1 (PPKCA1; 104100), Wang et al. (2015) identified heterozygosity for a missense mutation in the GJA1 gene (G8V; 121014.0023). The mutation segregated with disease in both families and was not found in 212 ethnically matched controls. Patch-clamp studies in transfected HEK293 cells demonstrated a gain-of-function effect with G8V hemichannels.
Erythrokeratodermia Variabilis et Progressiva 3
By exome sequencing in 3 unrelated patients with erythrokeratodermia variabilis et progressiva (see EKVP3; 617525), Boyden et al. (2015) identified heterozygosity for 2 de novo missense mutations in the GJA1 gene, E227D (121014.0024) and A44V (121014.0025). The mutations were not present in any of the unaffected parents available (1 patient was adopted), in approximately 2,500 control exomes, or in public databases of human genetic variation. Immunostaining of patient skin and transfected HeLa cells showed that, in contrast to wildtype connexin-43 (CX43), mutant CX43 did not localize to the membrane but appeared to be retained in the Golgi apparatus.
Associations Pending Confirmation
Connexin-43 is the major protein of gap junctions in the heart, and gap junctions are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. CX43 is targeted by several protein kinases that regulate myocardial cell-cell coupling. Britz-Cunningham et al. (1995) hypothesized that mutations altering sites critical to this regulation would lead to functional or developmental abnormalities of the heart. In 25 normal subjects and in 23 of 30 children with various forms of congenital heart disease, they found no amino acid substitutions in connexin-43. All 6 children with syndromes that included complex heart malformations had substitutions of one or more phosphorylatable serine or threonine residues. In 4 of these children, Britz-Cunningham et al. (1995) found 2 independent mutations, suggesting an autosomal recessive disorder. Five of the children had substitutions of proline for serine at position 364.
In 15 patients with sporadic defects of laterality and 3 with familial defects of laterality, Casey and Ballabio (1995) amplified and sequenced the region of CX43 that codes for the cytoplasmic tail. They stated that all of the nucleotides reported by Britz-Cunningham et al. (1995) were contained within this portion of the gene. The patients with familial defects of laterality were from kindreds with apparent autosomal dominant transmission of the trait. Casey and Ballabio (1995) detected no base changes in the coding sequence in any of the patients studied. Specifically, none of the base substitutions reported by Britz-Cunningham et al. (1995), including the ser364-to-pro mutation, were identified. Splitt et al. (1995) likewise sequenced the terminal 500 basepairs of the CX43 gene in 12 patients with defects of laterality and detected none of the mutations found by Britz-Cunningham et al. (1995) or any other mutations. One patient had an affected sib and 5 were from an inbred Pakistani population and had consanguineous parents, making an autosomal recessive defect likely. In their reply to the previous letters, Fletcher et al. (1995) pointed out that, in their previous studies (i.e., Britz-Cunningham et al. (1995)), all but 1 of their children with a ser364-to-pro substitution had polysplenia or asplenia and either pulmonary atresia or stenosis. They noted that the latter 2 features may be important in view of the fact that pulmonary atresia has consistently been found in mice with a CX43 gene 'knockout' (Reaume et al., 1995). In addition, the formation of the pulmonary outflow tract involves neural crest tissue which expresses high levels of connexin-43.
Several groups were unable to find CX43 mutations in patients with heterotaxy. Gebbia et al. (1996) studied a total of 38 cases of sporadic and familial heterotaxy and found no mutation in CX43. Penman Splitt et al. (1997) found no mutations in 48 patients with visceroatrial heterotaxy attending U.K. Regional Paediatric Cardiology Centres. Debrus et al. (1997) screened the entire coding sequence and direct flanking sequences of the CX43 gene in a selected group of 25 patients (19 familial cases) with a wide variety of lateralization defects and cardiovascular malformations. They detected only a single basepair insertion in the 3-prime untranslated region of 1 patient. To test the possibility of mutations in other parts of the CX43 gene, the gene was located on the physical map of chromosome 6, and flanking polymorphic markers were genotyped. Haplotype analysis excluded the CX43 gene locus in nearly all of the familial cases of lateralization defects. Thus, the results of Debrus et al. (1997) did not support the suggestion that this gene is implicated in human autosomal recessive lateralization defects. On the basis of analysis in the 3 previous reports and in 11 patients of their own, Toth et al. (1998) concluded that 'it is more and more likely that the results reported by Britz-Cunningham et al. (1995) were a laboratory artifact.' There had been a total of 78 cases of heterotaxy in which no CX43 mutation could be found in the 200 basepairs containing all of the nucleotide changes reported by Britz-Cunningham et al. (1995). See 306955 for a discussion of X-linked visceral heterotaxy.
Mutations in 4 members of the connexin gene family have been shown to underlie distinct genetic forms of deafness, including CX26 (GJB2), CX31 (GJB3; 603324), CX30 (GJB6; 604418), and CX32 (GJB1). Although Liu et al. (2001) reported that alterations in GJA1 cause a common form of deafness (607197) in African Americans and identified 2 different mutations (leu11 to phe and val24 to ala) in 4 of 26 African American probands, Paznekas et al. (2003) cited a personal communication from the senior author of the paper by Liu et al. (2001) indicating that the 2 mutations actually involve the pseudogene of connexin-43 on chromosome 5.
For discussion of a possible association between variation in the GJA1 gene and hypoplastic left heart syndrome (see 241550) or atrioventricular canal defects (see 606215), see 121014.0011.
In a Dutch kindred with ODDD and palmoplantar keratoderma, van Steensel et al. (2005) identified a 2-bp deletion in the GJA1 gene (121014.0010). The authors stated that this was the first reported mutation affecting the C-terminal loop, and suggested that the mutation might explain the presence of skin symptoms.
Vreeburg et al. (2007) reported another Dutch woman with ODDD and palmar hyperkeratosis with a 2-bp deletion in the GJA1 gene (121014.0015) resulting in premature termination of the protein and absence of a significant portion of the C-terminal domain. The findings suggested a genotype/phenotype correlation between pronounced palmoplantar keratoderma and mutations that truncate the C terminus of the GJA1 protein.
By targeted mutagenesis of connexin-43, Reaume et al. (1995) showed that its absence was compatible with survival of mouse embryos to term, even though cell lines mutant in Cx43 showed reduced dye coupling in vitro as assessed by injection of carboxyfluorescein. The latter test indicated a reduction, but not complete absence, of junctional communication. However, mutant embryos died at birth as a result of a failure in pulmonary gas exchange caused by a swelling and blockage of the right ventricular outflow tract from the heart. Reaume et al. (1995) interpreted this finding as indicating that Cx43 plays an essential role in heart development but that there is functional compensation among connexins in other parts of the developing fetus.
Ya et al. (1998) delineated the abnormal cardiac morphogenetic process in mice homozygous for CX43 deficiency. The major abnormality was a delay in the normal looping of the ascending limb of the heart tube, which includes the right ventricle and the outflow tract. This predisposes to subsequent complex malformation of the subpulmonary outflow tract and tricuspid valve, leading to the heart defects described by Reaume et al. (1995).
Guerrero et al. (1997) demonstrated that ventricular epicardial conduction of paced beats in the hearts of neonatal mice heterozygous for a targeted deletion of CX43 was 30% slower than that of wildtype, and 44% slower than that of wildtype in 6- to 9-month-old mice. They also found prolongation of the QRS complex in adult heterozygotes. Attempts to record from neonatal homozygous mutant mice were unsuccessful.
Using the Cre/loxP system and homologous recombination, Liao et al. (2001) generated mice with a vascular endothelial cell-specific deletion of the Cx43 gene that survived to maturity. Blood pressure and heart rate measurements were significantly lower in the Cx43 knockout mice than in floxed Cx43 or heterozygous mice. Nitric oxide (NO) levels were significantly higher in the heterozygous and homozygous mice, while angiotensin I and II (see 106150) levels were significantly higher in the homozygotes compared with the heterozygotes and the floxed Cx43 mice. Liao et al. (2001) concluded that this model has important implications for the understanding of cardiovascular function. They suggested that deletion of CX43 gap junctions in endothelium causes a primary rise in NO that tends to lower blood pressure and that angiotensin II levels are elevated as a secondary event.
By analysis of a developmental series of morphologically staged mouse embryos using whole-mount in situ hybridization, Richardson et al. (2004) demonstrated a strong correlation between the spatiotemporal expression pattern of Gja1 in the developing craniofacial complex and limbs and the pleiotropic features of ODDD.
Maass et al. (2004) generated mice lacking the C-terminal region of connexin-43, designated Cx43K258stop; more than 97% of the mice died shortly after birth due to a defect of the epidermal barrier involving perturbation of the terminal differentiation of keratinocytes. In contrast to Cx43-deficient mice, neonatal Cx43K258stop hearts showed no lethal obstruction of the right ventricular outflow tract, but signs of dilatation; 20% had repolarization abnormalities on electrocardiography. The very rare adult Cx43K258stop mice showed compensation of the epidermal barrier defect but persistent impairment of cardiac function on echocardiography. Female Cx43K258stop mice were infertile due to impaired folliculogenesis.
Kalcheva et al. (2007) created a mouse model of ODDD by generating mice heterozygous for the human I130T mutation, previously identified by Paznekas et al. (2003) in a family with ODDD and an increased incidence of cardiac arrhythmias. Cx43 was markedly reduced in mutant hearts with preferential loss of phosphorylated forms, resulting in interference with trafficking and with assembly of gap junctions in the junctional membrane. Dual whole-cell patch-clamp studies showed significantly lower junctional conductance between neonatal cell pairs from mutant hearts, and optical mapping of isolated perfused hearts with voltage-sensitive dyes demonstrated significant slowing of conduction velocity. Programmed electrical stimulation revealed a markedly increased susceptibility to spontaneous and inducible ventricular tachyarrhythmias. Kalcheva et al. (2007) concluded that the I130T mutation interferes with posttranslational processing, resulting in diminished cell-cell coupling, slowing of impulse propagation, and a proarrhythmic substrate.
Dobrowolski et al. (2009) generated mice expressing the human point mutation Cx43G138R and Cx43-knockout mice. Both conditional mouse models developed syndactylies as a consequence of disturbed interdigital apoptosis, which were due to reduced expression of two key morphogens: sonic hedgehog (SHH; 600725) and bone morphogenetic protein-2 (BMP2; 112261). Diminished levels of Bmp2 and subsequent upregulation of fibroblast growth factors (Fgfs) lead to an insufficient induction of interdigital apoptosis. The reduction of Shh expression in Cx43 mutants began on embryonic day 10.5 indicating a disturbance of the Fgf/Shh regulatory feedback loop, and confirming that gap junctions can relay Fgf signals to neighboring cells. Dobrowolski et al. (2009) concluded that Cx43-mediated gap junctional coupling in the mesenchyme of limb buds after embryonic day 11 is essential to maintain Shh expression, which in turn regulates the downstream signaling of Bmp2. Besides diminished interdigital apoptosis, the decreased expression of Bmp2 in Cx43 mutants may also be involved in other morphologic alterations in patients with ODDD.
To understand causal links between GJA1 mutations and glaucoma in individuals with ODDD, Tsui et al. (2011) examined the ocular phenotype of Gja1(Jrt/+) mice harboring a Cx43 G60S mutation. Decreased Cx43 protein levels were evident in whole eyes from mutant mice compared with those of wildtype mice at postnatal day 1. Cx43 immunofluorescence in ciliary bodies of mutant mice was diffuse and intracellular, unlike the gap junction plaques prevalent in wildtype mice. Intraocular pressure (IOP) in the mutant mice changed during postnatal development, with significantly lower IOP at 21 weeks of age in comparison to the IOP of wildtype eyes. Microphthalmia, enophthalmia, anterior angle closure, and reduced pupil diameter were observed in the mutant mice of all ages examined. Ocular histology showed prominent separations between the pigmented and nonpigmented ciliary epithelium of mutant mice, split irides, and alterations in the number and distribution of nuclei in the retina. Tsui et al. (2011) concluded that detailed phenotyping of the eyes of Gja1(Jrt/+) mice offered a framework for elucidating human ODDD ocular disease mechanisms and for evaluating new treatments.
Using Cx43 -/- mice and an automated voided-stain-on-paper method to measure micturition, Negoro et al. (2012) showed that Cx43 and the circadian clock regulate functional bladder capacity. Cx43 was among the oscillating genes whose expression was regulated by circadian clock genes, such as Cry1 (601933) and Cry2 (603732), in mouse bladder. Expression of Cx43 mRNA peaked at the end of the sleep phase. Increased and decreased Cx43 protein levels correlated with decreased and increased urine volume voided per micturition, respectively, in wildtype mice. Chromatin immunoprecipitation analysis demonstrated that Cx43 expression was positively regulated by Rev-Erb-alpha (NR1D1; 602408) interacting with Sp1 (189906) at Sp1 elements in the Cx43 promoter. Negoro et al. (2012) concluded that rhythmic regulation through the CX43 promoter is a mechanism induced by the clock for circadian oscillation of CX43 expression in bladder smooth muscle cells, and that this regulation contributes to the changes in bladder capacity, with an increase in sleep phase and a decrease in active phase.
In a case of oculodentodigital dysplasia (ODDD; 164200) in a family previously studied by Rajic and deVeber (1966) and Boyadjiev et al. (1999), Paznekas et al. (2003) found heterozygosity for a 50A-C transversion in the GJA1 gene, predicted to cause a tyr17-to-ser (Y17S) substitution.
In a family with oculodentodigital dysplasia (ODDD; 164200) studied by Judisch et al. (1979), Paznekas et al. (2003) found that an affected individual had a 52T-C transition in the GJA1 gene, predicted to result in a ser18-to-pro (S18P) substitution.
In a sporadic case of oculodentodigital dysplasia (ODDD; 164200) with involvement of only the fourth and fifth fingers (syndactyly type III; see 186100), Paznekas et al. (2003) identified a 61G-A transition in the GJA1 gene, predicted to result in a gly21-to-arg (G21R) substitution in the first transmembrane domain.
In a sporadic case of oculodentodigital dysplasia (ODDD; 164200) with involvement of only the fourth and fifth fingers (syndactyly type III; see 186100) reported by Traboulsi and Parks (1990), Paznekas et al. (2003) found a 65G-A transition in the GJA1 gene, predicted to result in a gly22-to-glu (G22E) substitution in the first transmembrane domain.
In a familial case of oculodentodigital dysplasia (ODDD; 164200) reported by Gellis and Feingold (1974) and Weintraub et al. (1975), Paznekas et al. (2003) found duplication of codon 52 (phe) of the GJA1 gene. Nucleotides 154-156 (TTT) were duplicated.
Brueton et al. (1990) described a family with type III syndactyly (186100) and a facial phenotype resembling that of oculodentodigital dysplasia (ODDD; 164200) but without any of the usual ophthalmologic, dental, or skeletal features commonly reported in ODDD. In affected members of the family reported by Brueton et al. (1990), Richardson et al. (2004) identified a 427G-A transition in the GJA1 gene, resulting in a gly143-to-ser (G143S) mutation in the cytoplasmic loop of the protein.
In affected members of a 5-generation Danish family with oculodentodigital dysplasia (ODDD; 164200), Kjaer et al. (2004) identified a 286G-A transition in exon 2 of the GJA1 gene, resulting in a val96-to-met (V96M) substitution. The mutation created a new cleavage site for the restriction enzyme Nde1.
In a Dutch kindred with oculodentodigital dysplasia (ODDD; 164200) and palmoplantar keratoderma, van Steensel et al. (2005) identified a 2-bp deletion (780T-G) in the GJA1 gene, resulting in a slightly truncated protein with 46 incorrect amino acids in the C-terminal cytoplasmic loop. The authors stated that this was the first reported mutation involving the C-terminal loop, and suggested that the mutation might explain the presence of skin symptoms.
This variant, formerly titled HYPOPLASTIC LEFT HEART SYNDROME 1 with an included title of ATRIOVENTRICULAR SEPTAL DEFECT 3, has been reclassified as a variant of unknown significance because its association with these phenotypes has not been confirmed.
In a blinded study, Dasgupta et al. (2001) analyzed the GJA1 gene in 46 controls and 20 heart transplant recipients using denaturing gradient gel electrophoresis (DGGE) to visualize normal and mutant DNAs, which were then separately sequenced. In 8 children with hypoplastic left heart syndrome (see HLHS1, 241550) and 1 with an atrioventricular canal defect (see 606215), they identified 4 identical substitutions on the same GJA1 allele: 2 missense mutations (R362Q and R376Q) and 2 silent polymorphisms at codons 353 and 374. All 4 of these substitutions are identical to the nucleotide sequence of the GJA1 pseudogene, suggesting the possibility of an illicit recombination. Results from in vitro phosphorylation studies indicated that the absence of arginines 362 and 376 completely abolishes phosphorylation in the GJA1 channel regulation domain. Analysis detected the presence of 3 GJA1 alleles in 1 patient (D2) with HLHS: 1 wildtype, another with the same 4 mutations as the other 8 patients, and a third with an S364P mutation, indicating likely somatic mosaicism. Dasgupta et al. (2001) noted that these mutations appeared to be acquired and not genetically transmitted, since they were absent from the genome of consanguineous family members of D2.
In affected members of an Italian family first reported by Vingolo et al. (1994) as having 'simple microphthalmos,' Vitiello et al. (2005) identified a heterozygous 581A-C transversion in the GJA1 gene, resulting in a his194-to-pro (H194P) substitution in a highly conserved residue within the second extracellular domain of the protein. The H194P substitution was predicted to dramatically alter the correct folding of the protein, preventing the formation of the entire connexon in a dominant-negative manner. On clinical reevaluation of the family, Vitiello et al. (2005) found extraocular signs that were highly suggestive of oculodentodigital dysplasia (ODDD; 164200). However, none of the patients had hand or foot syndactyly or any neurologic signs.
Kelly et al. (2006) studied a 13-year-old girl with oculodentodigital dysplasia (ODDD; 164200), her unaffected parents, and 3 unaffected sibs. The patient had a beak-like nose with hypoplasia of the alae nasi, anteverted nostrils, and prominent columella. Microphthalmia, hypertelorism, and prominent medial epicanthal folds were present. Scalp hair was short with curly-kinky texture, and there was marked hypoplasia of the dental enamel with yellow-colored teeth. Discrete follicular hyperkeratosis was noted on the extensor surfaces of the extremities, as well as mild palmoplantar keratoderma. Kelly et al. (2006) demonstrated a heterozygous missense mutation of the GJA1 gene: a T-to-C transition at nucleotide 32, predicted to lead to a nonconservative replacement of leucine 11 (CTT) with a proline residue (CCT) in the cytoplasmic amino terminus of CX43.
In a young Dutch woman with oculodentodigital dysplasia (ODDD; 164200) and palmar hyperkeratosis, Vreeburg et al. (2007) identified a 2-bp deletion (679delAT) in the GJA1 gene, resulting in a frameshift and premature termination of the protein, and absence of a significant portion of the C-terminal domain. The authors noted that van Steensel et al. (2005) had identified a deletion in the GJA1 gene (121014.0010) affecting the C-terminal loop in another Dutch kindred with ODDD and palmoplantar keratoderma. The findings suggested a genotype/phenotype correlation between pronounced palmoplantar keratoderma and mutations that truncate the C terminus of the GJA1 protein.
In 2 sisters with autosomal recessive oculodentodigital dysplasia (257850), the offspring of consanguineous Pakistani parents, Richardson et al. (2006) identified homozygosity for a C-to-T transition in the GJA1 gene resulting in an arg33-to-ter (R33X) substitution. The mutation is predicted to truncate GJA1 halfway through the first of 4 transmembrane domains, rendering the protein functionless. The parents were heterozygous for the mutation, which was not found in a panel of 50 control alleles. The authors noted that this was the first nonsense mutation identified in ODDD.
In a patient originally reported by Damiano Salpietro et al. (2004) as having Hallermann-Streiff syndrome (HSS; 234100) but who 'clearly had oculo-dento-digital syndrome' (257850) according to Hennekam et al. (2010), Pizzuti et al. (2004) identified a homozygous 227G-A transition in the GJA1 gene, resulting in an arg76-to-his (R76H) substitution. The clinically normal parents were heterozygous carriers of the mutation. Pizzuti et al. (2004) had hypothesized that homozygous hypomorphic mutations in GJA1 can result in a phenotype in an HSS/ODDD spectrum.
In a patient with oculodentodigital dysplasia (ODDD; 164200), Paznekas et al. (2003) identified a heterozygous C-to-A transversion in the GJA1 gene resulting in an arg76-to-ser (R76S) substitution in the first extracellular loop of the protein. R76 is a highly conserved residue in GJA1 of various species. In addition to the usual characteristics of ODDD, the patient had epilepsy.
In a patient with typical features of oculodentodigital dysplasia (ODDD; 164200) and the additional features of optic nerve and retinal dysplasia and ciliary body cysts, Gabriel et al. (2011) identified heterozygosity for an in-frame 12-bp deletion at nucleotide 120 in exon 2 of the GJA1 gene, leading to the elimination of 4 amino acids at positions 41-44. The mutation occurred in the phylogenetically conserved first transmembrane domain. The patient's father, paternal grandmother, and paternal aunt were known to have ODDD based on clinical examination, but they did not agree to molecular testing.
In a patient with typical features of oculodentodigital dysplasia (ODDD; 164200) and the additional features of optic nerve and retinal dysplasia, Gabriel et al. (2011) identified a de novo heterozygous 31C-T transition in the GJA1 gene, resulting in a leu11-to-phe (L11F) substitution (which the authors incorrectly stated as a substitution of a leucine for a phenylalanine) in the first intracellular domain. Gabriel et al. (2011) noted that this mutation had previously been reported by Jamsheer et al. (2009) in a patient with ODDD and a different ocular phenotype (microcornea, esotropia, and small pale discs of the optic nerves). Jamsheer et al. (2009) stated that leu11 is highly conserved among several species.
In affected members of 3 unrelated consanguineous families with craniometaphyseal dysplasia (CMDR; 218400), including a Brazilian family previously reported by Iughetti et al. (2000), a Portuguese family, and an Indian family, Hu et al. (2013) identified homozygosity for a c.716G-A transition in exon 2 of the GJA1 gene, resulting in an arg239-to-gln (R239Q) substitution at a highly conserved residue within a putative tubulin (see 602529)-binding motif in the intracellular C-terminal domain proximal to the fourth transmembrane domain. The mutation, which was also detected in a sporadic Brazilian CMD patient, segregated with disease in each family, and was not found in the dbSNP, HGMD, 1000 Genomes Project, or NHLBI Exome Sequencing Project databases.
In a 40-year-old woman with oculodentodigital dysplasia (ODDD; 164200) and lymphedema of the lower limbs, Brice et al. (2013) identified heterozygosity for a c.617A-G transition in exon 2 of the GJA1 gene, resulting in a lys206-to-arg (K206R) substitution at a highly conserved residue in a functional domain. The mutation, which segregated with disease in the family, was not found in 600 controls.
In an affected Chinese father and daughter and an unrelated Chinese boy with palmoplantar keratoderma and congenital alopecia-1 (PPKCA1; 104100), Wang et al. (2015) identified heterozygosity for a c.23G-T transversion in the GJA1 gene, resulting in a gly8-to-val (G8V) substitution at a highly conserved residue. The mutation was not found in the unaffected paternal grandparents in the first family, in the unaffected parents and sibs in the second family, in 212 ethnically matched controls, or in the Beijing Genomics Institute (BGI), 1000 Genomes Project, or HapMap8 databases. Studies in transfected HEK293 cells demonstrated that the G8V mutant forms functional gap junctions. Patch-clamp analysis revealed that the current density with G8V hemichannels was significantly larger than wildtype connexin-43 (CX43), suggesting gain-of-function hemichannel activity; intracellular fluorescence studies confirmed significantly increased Ca(2+) influx at resting potential with the mutant hemichannel compared to wildtype. Transfected HEK293 cells showed a significantly higher death rate than those expressing wildtype CX43, and increasing the extracellular Ca(2+) concentration rescued the cells in a dose-dependent manner. In addition, patient epidermis showed significantly larger numbers of apoptotic keratinocytes by TUNEL assay than control skin.
In a 2.5-year-old boy and an unrelated 6-year-old girl with erythrokeratodermia variabilis et progressiva (EKVP3; 617525), Boyden et al. (2015) identified heterozygosity for a de novo c.681A-T transversion (c.681A-T, NM_000165) in the GJA1 gene, resulting in a glu227-to-asp (E227D) substitution at a highly conserved residue at the intracellular boundary of the fourth transmembrane domain. The mutation was not found in the boy's parents (the girl was adopted), in approximately 2,500 control exomes, or in public databases of human genetic variation. Immunostaining of patient and control skin as well as transfected HeLa cells showed that, in contrast to wildtype CX43, the E227D mutant did not localize to the membrane but appeared to be retained in the Golgi apparatus.
In a 30-year-old woman with erythrokeratodermia variabilis et progressiva (EKVP3; 617525), Boyden et al. (2015) identified heterozygosity for a de novo c.131C-T transition (c.131C-T, NM_000165) in the GJA1 gene, resulting in an ala44-to-val (A44V) substitution at a highly conserved residue at the extracellular boundary of the first transmembrane domain. The mutation was not found in the unaffected parents, in approximately 2,500 control exomes, or in public databases of human genetic variation. Immunostaining of patient and control skin as well as transfected HeLa cells showed that, in contrast to wildtype CX43, the A44V mutant did not localize to the membrane but appeared to be retained in the Golgi apparatus.
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