Original Article
Somatic Mutations in the Connexin 40 Gene (GJA5) in Atrial Fibrillation
N Engl J Med 2006; 354:2677-2688June 22, 2006
- Abstract
Background
Atrial fibrillation is the most common type of cardiac arrhythmia and a leading cause of cardiovascular morbidity, particularly stroke. The cardiac gap-junction protein connexin 40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria. We hypothesized that idiopathic atrial fibrillation has a genetic basis and that tissue-specific mutations in GJA5, the gene encoding connexin 40, may predispose the atria to fibrillation.
Methods
We sequenced GJA5 from genomic DNA isolated from resected cardiac tissue and peripheral lymphocytes from 15 patients with idiopathic atrial fibrillation. Identified GJA5 mutations were transfected into a gap-junction–deficient cell line to assess their functional effects on protein transport and intercellular electrical coupling.
Results
Four novel heterozygous missense mutations were identified in 4 of the 15 patients. In three patients, the mutations were found in the cardiac-tissue specimens but not in the 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 germ-line origin. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling.
Conclusions
Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling. Our data suggest that common diseases traditionally considered to be idiopathic may have a genetic basis, with mutations confined to the diseased tissue.
Media in This Article
Figure 1
Detected Substitutions in Connexin 40 in Patients with Idiopathic Atrial Fibrillation.Figure 2
Differential Localization of Connexin 40 Mutants in N2A Cells.Article Activity
- Article
Atrial fibrillation is characterized by rapid, erratic electrical activation of the atrial myocardium, resulting in the loss of effective contractility, an increased likelihood of clot formation, and an increased risk of stroke.1 The rapid atrial activity may be conducted to the ventricles, resulting in the deterioration of heart function. In addition to causing substantial morbidity, atrial fibrillation confers an increased risk of mortality that is independent of coexisting risk factors.2 In the United States, more than 2 million adults have atrial fibrillation, with the prevalence increasing with age (5.9 percent among those older than 65 years).3 Thus, the socioeconomic burden of managing this disease is considerable.4
Studies investigating a molecular pathogenesis of atrial fibrillation have focused on familial forms of the disease. Recently, a mutation in KCNQ1, a potassium-channel gene also implicated in a form of the long-QT syndrome, was identified as the molecular basis of autosomal dominant atrial fibrillation in a single family from China.5 Two additional families with autosomal dominant atrial fibrillation have been identified and the loci mapped to 10q22–q24 and 6p14–p16.6,7 However, a causal gene has not been identified. Although the study of rare, familial forms of atrial fibrillation may provide insight into the molecular pathways involved in these selective cases of the disease, the genetic defects identified may not be representative of the pathogenesis in the more common, nonfamilial form.
Idiopathic forms of disease are traditionally not considered genetic in origin. However, somatic mutations are increasingly being identified as the cause of sporadic cases of disease in humans.8,9 Though somatic mutations are mostly recognized as a factor in the genetics of cancer, recent studies have confirmed the presence of somatic mutations that give rise to nonmalignant disease.10,11 We hypothesized that idiopathic atrial fibrillation has a genetic basis and that mutations predisposing the atria to fibrillation are somatic in nature. We focused on GJA5, the gene encoding connexin 40, a gap-junction protein with gene expression restricted principally to atrial tissue in humans. Connexin 40 gap junctions play a critical role in mediating atrial conduction through electrical coupling between cells, and GJA5-knockout mice have increased vulnerability to atrial reentrant arrhythmias.12,13 Furthermore, recent data suggest that sequence variations in potential regulatory regions of GJA5 may increase the risk of atrial fibrillation.14
Methods
Study Subjects
We obtained archival tissue specimens from 15 patients with idiopathic atrial fibrillation who had undergone surgical isolation of the pulmonary veins between 1998 and 2002 at the London Health Science Center, London, Ontario. These patients had an early age at onset of atrial fibrillation (average, 45 years), atrial fibrillation that was refractory to multiple medications, and no evidence of coronary artery, valvular, or hypertensive heart disease. All 15 patients provided blood samples for further DNA analysis. Lymphocyte DNA from 120 healthy persons and cardiac tissue obtained at the time of cardiac surgery from 50 patients without a history of atrial fibrillation were analyzed as controls. All study subjects were of Western European descent. All samples used in this study were collected after written informed consent had been obtained from the study subjects and were approved for study by the institutional review boards of the University of Western Ontario and the University of Ottawa Heart Institute.
Detection and Confirmation of Mutations
Genomic DNA was isolated from cardiac-tissue specimens according to the phenol–chloroform method. The coding region of GJA5 was amplified with the use of the polymerase chain reaction (PCR). Mutation screening was performed with the use of direct sequencing. To confirm somatic mutations, genomic DNA and total RNA from the cardiac-tissue specimens were extracted independently according to a silica-gel–column method (DNAeasy Tissue Kit and RNAeasy Micro Kit, Qiagen). An additional step of probe sonication was performed to enhance RNA extraction.
For the genomic DNA, PCR products were subcloned into the pGEM-T vector (Promega) and mutations were confirmed by restriction-digest analysis, direct sequencing, or both. For RNA, after reverse-transcriptase PCR was performed, mutations were confirmed by direct sequencing of the complementary DNA (cDNA). All sequencing was performed on an ABI 3100 DNA sequencer.
Protein-Transport Experiments
GJA5 mutations were introduced into a wild-type GJA5 clone by site-directed mutagenesis with the use of a mutagenesis kit (QuickChange, Stratagene). Clones were sequenced to confirm the mutation and exclude any other sequence variants. For localization experiments, wild-type and mutant GJA5 were tagged with green fluorescent protein (GFP). GFP-tagged wild-type or mutant GJA5 cDNA was transfected into neuroblastoma (N2A) cells, a gap-junction–deficient cell line. The connexin 40 expressed in the transfected N2A cells was immunolabeled with a 1:100 dilution of anti–connexin 40 antibody (Chemicon) followed by anti-IgG conjugated with Texas Red (Jackson ImmunoResearch Laboratories). Cells were viewed by confocal microscopy.
Immunohistochemical Analysis
Immunohistochemical analysis was performed on sections (7 μm thick) of atrial cardiac tissue fixed in formalin and embedded in paraffin. Tissue sections were deparaffinized, and antigens were retrieved by placing them in a microwave oven for 12.5 minutes in a citrate buffer (pH 5.6). The specimens were then blocked in 1:20 normal horse serum and incubated with 1:100 anti–connexin 40 antibody. The primary antibody was then detected with the diaminobenzidine chromagen system (Dako).
Electrophysiological Experiments
To assess protein function, we selected pairs of N2A cells with visible plaques at the cell–cell junction. Dual whole-cell voltage-clamp recordings were carried out at room temperature. To simulate the effect of heterozygosity and to evaluate the effect of the mutant connexin 40 protein on other cardiac connexins, we injected oocytes of the genus xenopus with complementary RNA (cRNA) for wild-type connexin 40, wild-type connexin 43, mutant connexin 40, or a mixture of wild-type and mutant connexin 40 cRNA in a 1:1 ratio, as previously described.15
Statistical Analysis
We used Fisher's exact test to analyze differences in the frequencies of coding-sequence variations between samples from patients with atrial fibrillation and samples from controls.
Results
Mutations
We identified four novel heterozygous mutations in GJA5 in 4 of the 15 patients with idiopathic atrial fibrillation (Table 1Table 1
Clinical Characteristics of Patients with Idiopathic Atrial Fibrillation and Status of Connexin 40 Mutation.). The mutations were in the highly conserved transmembrane-spanning domains of the connexin 40 protein (Figure 1AFigure 1Detected Substitutions in Connexin 40 in Patients with Idiopathic Atrial Fibrillation.). A 262C→T mutation, predicting the substitution of serine for proline at codon 88 (Pro88→Ser), was identified in two patients (Figure 1B). An additional patient had two nonallelic mutations, as determined by subcloning, resulting in Met163→Val (487A→G) and Gly38→Asp (113G→A) substitutions (Figure 1C and 1D, respectively). These mutations were detected in genomic DNA and RNA isolated from cardiac-tissue specimens. However, sequenced DNA from lymphocytes from these three patients showed no evidence of mutation, indicating a somatic source of the genetic defects (Table 2Table 2
Connexin 40 Clones from Patients with Somatic Mutations.). The Pro88 residue, located in the second transmembrane domain of connexin 40, is conserved evolutionarily in mammalian and zebrafish connexins (Figure 1F). An identical Pro88→Ser substitution in connexin 32 and connexin 50, resulting in dominantly inherited Charcot–Marie–Tooth disease and cataract disease, respectively, has been reported in five unrelated families.16-20 Similarly, Met163 substitutions in connexin 26 have been associated with hereditary deafness.21,22 Cardiac-tissue specimens from a fourth patient had a 286G→T mutation, predicting an Ala96→Ser substitution (Figure 1E). This sequence variant was also identified in lymphocyte DNA, indicating a germ-line origin. The GJA5 genes from the patient's immediate family members were sequenced. The variant was absent in the patient's three siblings and wife but was present in his two sons, who did not have a history of atrial fibrillation. However, on surface electrocardiography, the carrier sons had an abnormally prolonged P-wave duration (>120 msec), a known predictor of atrial fibrillation23 (Figure 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org). The variant was also identified in the lymphocyte DNA from one 48-year-old control subject (population frequency, 0.6 percent). Long-term follow-up of asymptomatic persons carrying the allele encoding Ser96 will be needed to confirm its clinical significance.
We also sequenced GJA1 (which encodes connexin 43) from cardiac-tissue specimens. No coding-region mutations were identified. To assess the prevalence of GJA5 mutations in randomly selected patients with nonvalvular atrial fibrillation, we sequenced DNA isolated from lymphocytes from 20 such patients. No coding-region mutations were identified, suggesting either that the prevalence of GJA5 defects is lower in a more random population of patients with atrial fibrillation than in a more specific subgroup of patients with idiopathic atrial fibrillation or that tissue-specific genetic analyses are needed to measure the prevalence more accurately.
A cross-species comparison of connexin 40 shows a homology of more than 80 percent between the DNA and amino acid sequences, reflecting the evolutionary conservation of the structures of the GJA5 gene and the connexin 40 protein (Figure 1F). The direct sequencing of 100 alleles from cardiac-tissue DNA and 240 alleles from lymphocyte DNA from controls showed no evidence of the Pro88→Ser, Met163→Val, or Gly38→Asp substitution, providing further support for a potentially pathogenetic role of these substitutions. Two other sequence variations were identified in lymphocyte DNA from the controls: 369C→T, which causes a Tyr123 silent mutation, and 377C→T, which causes a Pro126→Leu substitution. Pro126 is deleted in the connexin 40 orthologue in rats and occurs within the cytoplasmic loop of connexin 40, a region of known variability among connexin proteins.12 The frequency of sequence variations in GJA5 was significantly higher in patients than in controls (P<0.001).
Transport of Connexin 40 Mutants
Wild-type and mutant connexin 40 were expressed in N2A cells, a gap-junction–deficient cell line. As expected, cells expressing wild-type connexin 40 were localized subcellularly to sites of cell–cell contact (Figure 2AFigure 2
Differential Localization of Connexin 40 Mutants in N2A Cells.). Cells expressing the Pro88→Ser mutant formed no visible gap-junction plaques and had intracellular retention of connexin 40 (Figure 2C). Similarly, a greater degree of intracellular localization and only sparse gap-junction plaques were evident in cells expressing the Gly38→Asp mutant protein (Figure 2I), as compared with the wild type. Expression of the Ala96→Ser variant was also localized intracellularly to a greater degree than that of wild-type connexin 40, but gap-junction plaques were present in similar amounts (Figure 2E). In contrast, the Met163→Val mutant protein exhibited a pattern of subcellular distribution (Figure 2G) similar to that of wild-type connexin 40.Immunohistochemical Staining of Atrial Tissue
Atrial-tissue specimens from controls and patients with atrial fibrillation who carried wild-type or mutant connexin 40 were stained with anti–connexin 40 antibody. Immunostaining showed that connexin 40 localization and gap-junction formation were indistinguishable in the atrial tissue of patients without GJA5 mutations (Figure 3BFigure 3
Localization of Connexin 40 and Formation of Gap Junctions in Atrial Tissue from Patients with Detected Mutations.) and in controls (Figure 3A). In contrast, atrial tissue from the two patients with the Pro88→Ser substitution consistently showed a mosaic pattern of abnormal gap-junction formation and intracellular retention of connexin 40 (Figure 3C). A similar pattern, although weaker, was evident in the atrial tissue of Patient 9, who had the nonallelic Gly38→Asp and Met163→Val substitutions (Figure 3D). The abnormal localization of connexin 40 in cardiac cells confirms an origin of the mutations in myocytes, as opposed to fibroblasts. Atrial tissue harboring the Ala96→Ser variant did not show any obvious abnormalities in connexin 40 distribution (Figure 3E).Electrophysiological Function of Mutant Connexin 40
The electrical-coupling properties of wild-type and mutant connexin 40 were recorded for the paired N2A cells that exhibited visible gap-junction plaques, when possible. No visible plaques were observed in cells expressing the GFP-tagged Pro88→Ser mutant, and as expected, there was no cell–cell coupling between cells (Figure 4AFigure 4
Effect of Pro88→Ser and Ala96→Ser Connexin 40 Mutations on Cell Coupling and the Activity of Wild-Type Connexins. and Table 3Table 3
Dual Whole-Cell Voltage-Clamp Recordings from N2A Cells Transfected with Human Wild-Type and Mutant Connexin 40.). In cell pairs expressing the Gly38→Asp mutant, cell–cell coupling occurred at a significantly lower junctional conductance than in wild-type connexin 40 cells (Table 3). However, in two cell pairs that had gap-junction plaques, the coupling conductances were similar to those of wild-type connexin 40 (data not shown), suggesting that the functional consequence of this mutation is related predominantly to impaired transport of the protein to the cell surface and reduced gap-junction formation, rather than to impaired coupling properties. In contrast, paired cells that formed visible gap-junction plaques and expressed the Ala96→Ser variant consistently demonstrated no or weak cell–cell coupling, as compared with wild-type connexin 40 (Table 3). The finding suggests that this variant significantly impairs functional cell–cell coupling. Paired cells expressing the Met163→Val mutant had cell-coupling properties similar to those of wild-type connexin 40 (Table 3), suggesting that this mutation may represent a benign polymorphism.To test the hypothesis that GJA5 mutants act as dominant negative inhibitors of wild-type connexin 40 activity, we compared the ability of wild-type connexin 40 and mutant connexin 40 to induce gap-junctional coupling in pairs of oocytes of the genus xenopus. Oocyte pairs expressing wild-type connexin 40 had high levels of coupling. In contrast, oocyte pairs expressing the Pro88→Ser mutant had no detectable coupling. Furthermore, the Pro88→Ser mutant completely inhibited the activity of coexpressed wild-type connexin 40 (Figure 4B, left-hand plot). The Ala96→Ser variant also had a marked reduction in gap-junctional coupling, as compared with wild-type connexin 40. The coexpression of Ala96→Ser and wild-type connexin 40 significantly inhibited the activity of wild-type connexin 40 (Figure 4B, center plot).
To determine whether mutant connexin 40 could interfere with the function of other cardiac connexins, oocytes were injected with a 1:1 mixture of cRNA for wild-type connexin 40 and wild-type connexin 43, either alone or in combination with an equal amount of cRNA for a connexin 40 mutant. Oocyte pairs injected with the mixture of wild-type connexin 43 and wild-type connexin 40 had high levels of gap-junctional coupling. When the Pro88→Ser or Ala96→Ser mutant was coexpressed with the mixture of wild-type connexins at a cRNA ratio of 2:1:1, the channel activity of both wild-type connexins was considerably reduced (Figure 4B, right-hand plot).
Discussion
We identified tissue-specific or somatic mutations in the GJA5 gene, which encodes connexin 40, in 3 of 15 patients with idiopathic atrial fibrillation. A fourth patient had a germ-line sequence variant. These patients had an early age at onset of atrial fibrillation, and clinical investigations had ruled out coexisting valvular or hypertensive heart disease.
Molecular mechanisms leading to tissue mosaicism include chimerism or spontaneous mutation in a progenitor-cell lineage. The possibility of chimerism was excluded in our study, since cardiac-tissue specimens (containing mutant cells) and lymphocytes from the same patient had identical polymorphic DNA markers (data not shown). Therefore, since myocardial cells do not divide, somatic mosaicism in cardiac tissue must have resulted from a somatic mutation in an early myocardial progenitor cell during embryogenesis.
Our results are supported by the finding of Lerman et al. of a somatic mutation of the G-protein subunit Gai2 in cardiac tissue that caused arrhythmia.24 Similar to our findings, the mutation was identified only in cardiac tissue and was absent in peripheral lymphocytes. Connexin-tissue mosaicism as a substrate for cardiac arrhythmia has also been demonstrated in chimeric connexin-43 mice.25 Chimeric mice with patchy myocardial expression of connexin 43 had discrete areas of conduction delay, which presumably were responsible for the observed reentrant cardiac arrhythmias in these animals.25 These data support the concept that tissue mosaicism of connexin 40 may be responsible for atrial arrhythmias in humans.
The functional relevance of the identified mutations was confirmed in protein localization experiments, by immunostaining of atrial tissue from patients, and in electrophysiological recordings of cell–cell coupling mediated by gap junctions. The immunostaining of atrial tissue from patients with the Pro88→Ser and Gly38→Asp substitutions confirmed the retention of intracellular connexin 40 and abnormal gap-junction formation present in a mosaic pattern, a finding consistent with somatic mutation in a subpopulation of cells. The Ala96→Ser variant appeared to result in the assembly of gap junctions between adjacent cells; however, these paired cells consistently demonstrated absent or weak cell–cell electrical coupling. The coexpression of mutant and wild-type connexin 40 in xenopus oocytes significantly impaired functional cell–cell coupling, confirming that mutant connexin 40 acts as a dominant negative inhibitor of wild-type connexin 40 activity. Since connexin 43 is expressed in atrial tissue in addition to connexin 40 and evidence suggests that connexin 40 and connexin 43 may form heteromeric channels,26 we confirmed that mutant connexin 40 also inhibits the functional coupling of wild-type connexin 43. Thus, genetic defects in GJA5 may induce a loss of function by means of two mechanisms: either impaired connexin transport and gap-junction assembly at the cell surface or the inhibition of cell–cell electrical coupling.
The Pro88→Ser substitution was identified in two unrelated patients. It is interesting that this substitution has been identified in connexin 32 and connexin 50, in which it has been shown to cause dominantly inherited Charcot–Marie–Tooth disease and cataract disease, respectively.16-20 Even more interesting is the fact that the same Pro88→Ser substitution has been identified in a naturally occurring strain of Caenorhabditis elegans that has abnormal electrical coupling in myocytes and a phenotype of uncoordinated locomotion.27,28 This is an example of a genetic mutation in a gene family associated with three different diseases in humans, in addition to a disease phenotype in an invertebrate species. Our data on the function of the Pro88→Ser mutant are consistent with those on the parallel Pro88→Ser substitution in connexin 50, which causes familial cataracts.15 Pro88 has been implicated previously as a key residue in the transduction of voltage gating in the connexin-protein family, further highlighting the biologic significance of this amino acid in connexin proteins.29,30
Studies involving high-resolution electrical mapping during atrial fibrillation have documented that multiple reentry circuits are a fundamental component of the perpetuation of the arrhythmia.31,32 The myocardial substrate for reentry initiation is dependent on regional variability in conduction velocity, which creates localized asymmetry in the depolarizing wavefront through the myocardium.33 A substrate with localized asymmetry in conduction promotes reentry, whereby depolarizing wavefronts continually reenter themselves, resulting in erratic and uncoordinated myocardial electrical activity. Since the cell–cell coupling of depolarizing current is mediated only at gap junctions, the biophysical properties of gap junctions are critical in ensuring normal myocardial conduction.12 Atrial myocardium harboring a population of cells containing mutant connexin 40 protein that adversely affect electrical coupling would give rise to regions of heterogeneous conduction in tissue, providing a substrate that predisposes the atria to microreentry arrhythmias.
As is the case for all known cardiac arrhythmias with a genetic basis, periods of arrhythmia are episodic, despite the presence of mutant protein within the myocardial tissue of affected patients from birth. The onset of genetically based arrhythmias requires physiological stressors to precipitate the arrhythmia, presumably by exacerbating the already abnormal myocardial electrophysiology in the presence of mutant protein. In idiopathic atrial fibrillation, a common precipitant is increased vagal tone, mediated by muscarinic receptors.34 The activation of muscarinic receptors has been shown to impair the cell–cell coupling mediated by gap junctions.35 Together with our data, this observation provides a possible mechanistic link between enhanced vagal tone, impaired cell–cell electrical coupling, and the development of paroxysmal atrial fibrillation.
Although we identified GJA5 mutations in 4 of 15 patients, our patients were highly selected and this prevalence may not be representative of the prevalence of GJA5 sequence variations in a more random cohort of patients with atrial fibrillation. Larger-scale studies of patients with atrial fibrillation who have an age-related onset and coexisting coronary artery, valvular, or hypertensive heart disease will provide important additional data that should be considered before our findings are generalized. However, our findings provide evidence of the critical role of connexin 40 in atrial electrophysiology and evidence of a new paradigm — that common diseases traditionally considered idiopathic may have a genetic basis, with mutations confined to the diseased tissue.
Supported in part by grants from the J.P. Bickell Foundation (to Dr. Gollob), the Heart and Stroke Foundation of Ontario (to Drs. Gollob and Krahn), Canada Research Chair Program (to Dr. Bai), the Canadian Institutes for Health Research (to Drs. Jones and Bai), and the National Institutes of Health (to Dr. Ebihara).
Drs. Jones, Krahn, and Gollob report having submitted a patent application for the Pro88→Ser connexin 40 substitution. No other potential conflict of interest relevant to this article was reported.
We are indebted to our patients for their dedicated support; to Ms. Megan Fortier, Mrs. Bonnie Spindler, Mr. Robbie Davies, Ms. Morette Wong, Ms. Wendy Pritchett, Dr. Subrata Charkrabarti, Mr. David Mallott, and Ms. Pierrette Bolongo for technical assistance; and to Dr. Hongling Wang for both technical assistance and constructing the connexin 40 model.
Source Information
From the Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.H.G., L.D., J.P.V., A.S.L.T., A.F.R.S., F.T.), and the Departments of Medicine (M.H.G., D.L.J., A.D.K., G.J.K., R.Y., A.C.S.), Physiology and Pharmacology (D.L.J., X.-Q.G., D.B.), Anatomy and Cell Biology (Q.S.), and Surgery (G.M.G.), University of Western Ontario, London, Ont. — both in Canada; and the Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, Ill. (X.L., L.E.).
Address reprint requests to Dr. Gollob at the Arrhythmia Research Laboratory and Division of Cardiology, University of Ottawa Heart Institute, Rm. H350, 40 Ruskin St., Ottawa, ON K1Y 4W7, Canada, or at mgollob@ottawaheart.ca.
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