Alternative titles; symbols
HGNC Approved Gene Symbol: GJA5
Cytogenetic location: 1q21.2 Genomic coordinates (GRCh38): 1:147,756,199-147,773,351 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.2 | Atrial fibrillation, familial, 11 | 614049 | Autosomal dominant | 3 |
| Atrial standstill, digenic (GJA5/SCN5A) | 108770 | Autosomal dominant | 3 |
Connexin proteins oligomerize to form intercellular channels, called gap junctions, through which ions and small molecules move between adjacent cells. See 121011 for a general discussion of the connexin gene family.
Kanter et al. (1992) demonstrated that canine ventricular myocytes express 3 distinct gap junction proteins, Cx40, Cx43 (GJA1; 121013), and Cx45. Kanter et al. (1994) used PCR with primers based on rat and dog Cx40 to clone human CX40. The CX40 gene encodes a predicted 358-amino acid protein whose sequence is 82% identical to that of the rat and mouse CX40 protein. Northern blot analysis showed that CX40 mRNA is expressed as an approximately 3.3-kb transcript in ventricular myocardium. In immunofluorescence studies, CX40 localized to intercalated disc regions of the left ventricle, which join cardiac myocytes and contain gap junctions.
Kaba et al. (2001) noted that cardiac myocytes are electrically coupled via gap junctions. Immunohistochemical staining of embryonic mouse and human fetal hearts localized CX40 at the superficial zones of trabeculae in developing ventricles. As development progressed, CX40 became largely confined to the conduction system.
By searching EST databases, Dupays et al. (2003) identified 2 CX40 splice variants that differed only in the 5-prime untranslated region. RT-PCR detected expression of the transcript utilizing exon 1A in endothelial cells, and the transcript utilizing exon 1B in normal placental cytotrophoblasts and in malignant cytotrophoblastic cell lines. Both transcripts were expressed in right atrial appendages and in all heart regions investigated, with higher levels in atrium. Transcripts including exon 1A predominated.
Dupays et al. (2003) determined that the CX40 gene contains 3 exons, which they designated 1A, 1B, and 2. Exons 1A and 1B are alternate 5-prime untranslated regions that appear to induce cell type-specific expression, and exon 2 is the coding exon. The entire gene spans about 25 kb. The DNA sequence upstream of exon 1A contains 7 SP1 (189906)-binding sites and potential binding sites for transcription factors that control vascular gene expression, such as ETS1 (164720) and GATA (see 305371), but no TATA or CAAT box. The region upstream of exon 1B is preceded by 3 CAAT boxes, 2 SP1-binding sites, and multiple binding sites for the basal transcription factors AP1 (see Jun, 165160) and AP4 (600743). Kanter et al. (1994) had noted 1 coding exon and a 5-prime untranslated exon, corresponding to exon 1A, in the CX40 genomic sequence.
Seul et al. (1997) characterized the structure of the mouse Cx40 gene.
Willecke et al. (1990) used a mouse cDNA probe in Southern analysis of mouse-human somatic cell hybrids to map the human CX40 and CX37 (GJA4) genes to 1pter-q12.
By fluorescence in situ hybridization, Gelb et al. (1997) mapped the GJA5 gene to chromosome 1q21.1 in a region that shows homology of synteny with mouse chromosome 3, where the mouse Gja5 gene maps.
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, 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.
Atrial Standstill 1
Groenewegen et al. (2003) reported a family in which 1 deceased and 3 living members had atrial standstill (ATRST1; 108770). They identified a mutation (D1275N; 600163.0034) in the SCN5A gene in all 3 affected living members and in 5 unaffected members; the deceased member was an obligate carrier. Eight family members were found to be homozygous for 2 closely linked polymorphisms within regulatory regions of the GJA5 gene: a -44G-A transition and a 71A-G transition. Only the 3 affected living members coinherited the SCN5A mutation and the 2 rare GJA5 polymorphisms. Functional analysis demonstrated a 65% reduction in promoter activity with the rare -44A/+71G GJA5 haplotype compared to the more common -44G/+71A haplotype. Groenewegen et al. (2003) proposed that atrial standstill in this family resulted from coinheritance of the SCN5A mutation and the rare GJA5 polymorphisms.
In a Japanese family in which an 11-year-old boy had sick sinus syndrome that progressed to atrial standstill, Makita et al. (2005) analyzed 3 cardiac ion channel genes previously associated with atrial standstill, atrial fibrillation, or sick sinus syndrome: SCN5A, HCN4 (605206), and GJA5. No mutations were found in HCN4, but the proband and his asymptomatic father were heterozygous for a missense mutation in SCN5A (L212P; 600163.0048). In addition, the proband and his unaffected mother and maternal grandmother were all heterozygous for the same 2 rare GJA5 polymorphisms identified by Groenewegen et al. (2003) in atrial standstill patients, -44A/+71G. Makita et al. (2005) suggested that defects in SCN5A underlie atrial standstill, and that coinheritance of GJA5 polymorphisms represents a possible genetic modifier of the clinical manifestations.
Familial Atrial Fibrillation 11
Gollob et al. (2006) presented evidence that tissue-specific mutations in the GJA5 gene may predispose the atria to fibrillation. They sequenced the GJA5 gene from genomic DNA isolated from resected cardiac tissue and peripheral lymphocytes from 15 patients with idiopathic atrial fibrillation (ATFB11; 614049). Four novel heterozygous missense mutations (see, e.g., 121013.0001-121013.0002) were identified in 4 of the 15 patients. In 3 patients, the mutations were found in cardiac tissue specimens but not in lymphocytes, indicating a somatic source of the genetic defects. In the fourth patient, the sequence variant was detected in both cardiac tissue and lymphocytes, suggesting a germline origin. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling.
Yang et al. (2010) performed direct sequencing of the coding region of the GJA5 gene in 126 unrelated Chinese probands with familial atrial fibrillation (AF) and identified a heterozygous nonsense mutation in 1 proband (121013.0003) that segregated with disease in the family.
Yang et al. (2010) analyzed the GJA5 gene in 218 unrelated Chinese probands with AF and identified 3 heterozygous missense mutations in 3 probands (121013.0004-121013.0006, respectively). The mutations, which all occurred at evolutionarily conserved residues, segregated with disease in each family and were not found in 200 ethnically matched controls.
Wirka et al. (2011) tested 8 SNPs within the CX40 region for association with CX40 levels measured in atrial tissue from 61 individuals who had undergone cardiac surgery, 85.2% of whom had a history of AF and 49.2% of whom had AF at the time of surgery. The previously described CX40 promoter 'A' SNP rs35594137 (-44G-A), which was in perfect linkage disequilibrium with the SNP rs1152588 (71A-G) in exon 1A, was not associated with CX40 mRNA levels. However, a common SNP rs10465885 located within the TATA box of an alternative CX40 promoter (promoter 'B') in exon 1B was strongly associated with CX40 mRNA expression (p less than 0.0001) and displayed strong and consistent allelic expression imbalance in human atrial tissue. A promoter-luciferase assay in culture mouse cardiomyocytes demonstrated reduced activity of the promoter containing the minor allele of this SNP (p less than 0.0001). Testing of both rs35594137 and rs10465885 for association with early-onset lone AF (onset at less than 60 years of age) in 384 cases and 3,010 controls revealed that the promoter B SNP rs10465885 was associated with early-onset lone AF (odds ratio, 1.18; p = 0.046), and metaanalysis of 2 additional early-onset lone AF case-control cohorts confirmed the association (odds ratio, 1.16; p = 0.022) with rs10465885. The promoter A SNP rs35594137, however, was not associated with the lone AF phenotype in any of the cohorts studied or in a combined analysis.
Sun et al. (2013) analyzed the GJA5 gene in 68 unrelated Chinese patients with isolated AF and identified a heterozygous missense mutation in 1 patient (I75F; 121013.0007). Dual voltage-clamp electrophysiologic analysis in N2A cells showed that there was no electrical coupling of cell pairs expressing I75F alone, and there was a significant reduction in gap junction coupling conductance when the mutant was coexpressed with wildtype CX40 or CX43 (GJA1; 121014). Analysis of another AF-linked CX40 mutant, L229M (121013.0006), showed no apparent coupling defect when the mutant was expressed alone or together with wildtype CX40, but L229M specifically reduced gap junction coupling when coexpressed with wildtype CX43.
Gu et al. (2003) generated Cx40 +/- and -/- mice to study the role of CX40 in cardiac morphogenesis. The overall incidence of cardiac malformations was 18% in heterozygotes and 33% in homozygotes; the malformations were more severe in homozygotes, and the incidence of malformations was even higher (44%) in the offspring of -/- matings. The most common malformations were of conotruncal origin, but endocardial cushion defects and other malformations were also found. Gu et al. (2003) concluded that CX40 is not essential for cardiogenesis, but its absence or limited expression increases the probability of cardiac malformations.
To study the role of gap junction communication in cardiac conduction, Simon et al. (1998) generated Cx40 null mice. Using electrocardiographic analysis, they showed that the null mice had cardiac conduction abnormalities characteristic of first-degree atrioventricular block with associated bundle branch block. Simon et al. (1998) concluded that gap junctions are essential for the rapid conduction of impulses in the His-Purkinje system.
In both atrial tissue and lymphocytes from a 41-year-old male with atrial fibrillation (ATFB11; 614049), Gollob et al. (2006) identified a 286G-T transversion in the GJA5 gene, predicted to cause an ala96-to-ser (A96S) substitution. The variant was absent in the patient's 3 sibs and wife but was present in his 2 sons, who had no history of atrial fibrillation; however, on surface electrocardiography, the carrier sons had an abnormally prolonged P-wave duration (more than 120 ms), a known predictor of atrial fibrillation (Dilaveris et al., 1998). The variant was also identified in lymphocyte DNA from a 48-year-old control subject (population frequency, 0.6%). Gollob et al. (2006) noted that long-term follow-up of asymptomatic persons carrying the ser96 allele was needed to determine the clinical significance of the variant.
In 2 unrelated subjects with atrial fibrillation (ATFB11; 614049), Gollob et al. (2006) identified a 262C-T transition in the GJA5 gene, predicted to cause a pro88-to-ser (P88S) substitution. The mutation was detected in atrial tissue but not in lymphocytes, indicating a probable somatic mutation. Gollob et al. (2006) noted that the pro88 residue, located in the second transmembrane domain of connexin-40, is highly conserved in mammalian and zebrafish connexins.
In 7 affected members of a Chinese family with paroxysmal or persistent atrial fibrillation (ATFB11; 614049), Yang et al. (2010) identified heterozygosity for a 145C-T transition in the GJA5 gene, resulting in a gln49-to-ter (Q49X) substitution that was predicted to cause premature termination and deletion of 3 transmembrane domains, 3 loop regions, and the C terminus. The mutation was detected in 6 additional affected family members, but was not found in 6 unaffected family members or in 200 ethnically matched controls.
In affected members of a 3-generation Chinese family segregating autosomal dominant atrial fibrillation (ATFB11; 614049), Yang et al. (2010) identified heterozygosity for a 253G-A transition in the GJA5 gene, resulting in a val85-to-ile (V85I) substitution at a highly conserved residue within the second transmembrane domain. The mutation was not found in 4 unaffected relatives or in 200 ethnically matched controls.
In affected members of a 2-generation Chinese family segregating autosomal dominant atrial fibrillation (ATFB11; 614049), Yang et al. (2010) identified heterozygosity for a 661C-A transversion in the GJA5 gene, resulting in a leu221-to-ile (L221I) substitution at a highly conserved residue within the fourth transmembrane domain. The mutation was not found in 4 unaffected relatives or in 200 ethnically matched controls.
In affected members of a 3-generation Chinese family segregating autosomal dominant atrial fibrillation (ATFB11; 614049), Yang et al. (2010) identified heterozygosity for a 685C-A transversion in the GJA5 gene, resulting in a leu229-to-met (L229M) substitution at a highly conserved residue within the cytoplasmic region near the fourth transmembrane domain. The mutation was not found in 4 unaffected relatives or in 200 ethnically matched controls.
Sun et al. (2013) performed dual voltage-clamp electrophysiologic analysis in N2A cells and observed no impairment in junctional conductance when the L229M mutant was expressed alone or together with wildtype CX40. However, there was a significant reduction in junctional conductance when L229M was coexpressed with CX43 (GJA1; 121014), suggesting a dominant-negative effect of the mutant on wildtype CX43 gap junction function.
In a 42-year-old Chinese woman with isolated atrial fibrillation (ATFB11; 614049), Sun et al. (2013) identified heterozygosity for a c.223A-T transversion in the GJA5 gene, resulting in an ile75-to-phe (I75F) substitution at a highly conserved residue located at the boundary of the first extracellular domain and the second transmembrane domain. The mutation was also detected in the patient's affected father but was not found in unaffected family members, in 200 controls, or in the dbSNP database. Dual voltage-clamp electrophysiologic analysis in N2A cells demonstrated no electrical coupling of cell pairs expressing the I75F mutant alone, and there was a significant reduction in gap junction coupling conductance when the mutant was coexpressed with wildtype CX40 or CX43 (GJA1; 121014). At the single-channel level, the I75F mutant reduced the total number of active channels without changing conductance of individual gap junction channels, and also altered transjunctional voltage-dependent gating properties.
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