Atrial Fibrillation, Familial, 11

A number sign (#) is used with this entry because of evidence that familial atrial fibrillation-11 (ATFB11) is caused by heterozygous mutation in the GJA5 gene (121013) on chromosome 1q21. Atrial fibrillation has also been associated with somatic mutation in the GJA5 gene.

Description

Atrial fibrillation is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997).

For a discussion of genetic heterogeneity of familial atrial fibrillation, see ATFB1 (608583).

Pathogenesis

Chaldoupi et al. (2009) reviewed the role of the connexin-40 (CX40, or GJA5) protein in atrial fibrillation (AF), noting that prolonged episodes of AF result in electrical and structural remodeling that favors the recurrence or perpetuation of AF. The electrical remodeling involves changes in CX40 expression and distribution, both in the atrial myocardium and in the thoracic veins (superior vena cava and pulmonary veins). Abnormal CX40 expression correlated with both trigger formation from the thoracic veins as well as enhanced vulnerability of the atrial myocardium to AF.

Molecular Genetics

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. Four novel heterozygous missense mutations (see, e.g., 121013.0001 and 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 mutation was detected in both cardiac tissue and lymphocytes, suggesting a germline origin.

Yang et al. (2010) analyzed the GJA5 gene in 126 unrelated Chinese probands with atrial fibrillation (AF) and identified a heterozygous nonsense mutation (121013.0003) in a 64-year-old female patient who was diagnosed with paroxysmal AF at 32 years of age, with episodes occurring as frequently as once a week, who also had right bundle branch block on electrocardiography. 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.

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 segregated with disease in all 3 families and were not found in 200 ethnically matched controls.

Wirka et al. (2011) tested GJA5 SNPs in promoter 'A' (rs35594137; -44G-A) and promoter 'B' (rs10465885; 26A-G) for association with early-onset lone AF (onset at less than 60 years of age) in 384 cases and 3,010 controls and found that the promoter B SNP rs10465885 was significantly associated with early-onset lone AF (odds ratio, 1.18; p = 0.046); metaanalysis of 2 additional early-onset lone AF case-control cohorts confirmed the association (odds ratio, 1.16; p = 0.022) with rs10465885.

Sun et al. (2013) analyzed the GJA5 gene in 68 unrelated Chinese patients with isolated AF and identified a heterozygous missense mutation (I75F; 121013.0007) in a 42-year-old woman who had been diagnosed at age 40 years. The mutation was also detected in her father, who had been diagnosed with lone AF at 41 years of age, but it was not found in unaffected family members, in 200 controls, or in the dbSNP database. The proband's deceased paternal grandfather had also been diagnosed with AF. Functional analysis demonstrated that the I75F mutant is unable to form functional gap junction channels and also impairs coupling when expressed with wildtype CX40 or CX43 (GJA1; 121014).