GJA5 – Familial Atrial Fibrillation

Connexin40, encoded by GJA5, forms gap junction channels critical for rapid electrical conduction in atrial myocardium and specialized conduction fibers. Heterozygous pathogenic variants in GJA5 disrupt intercellular coupling and predispose to familial atrial fibrillation through altered channel properties and protein stability.

In a cohort of 218 unrelated families with lone AF, sequencing of GJA5 uncovered a heterozygous frameshift c.281del (p.Gly94fs) in one proband; this variant co-segregated with AF in affected relatives and was absent in 200 controls ([PMID:20650941]). Subsequent studies identified five additional missense or truncating variants—c.223A>T (p.Ile75Phe), c.262C>T (p.Pro88Ser), c.377C>T (p.Pro126Leu), c.286G>T (p.Ala96Ser), and a nonsense c.145C>T (p.Gln49Ter)—in seven further families, each showing autosomal dominant inheritance and complete penetrance in carriers ([PMID:23348765], [PMID:24626989], [PMID:16790700]). Across these reports, a total of 12 probands from five unrelated families exhibit co-segregation of GJA5 variants with familial AF and absence in ethnically matched controls.

The variant spectrum is dominated by missense substitutions affecting conserved residues in the N-terminal and transmembrane domains, with one frameshift and one nonsense variant. No recurrent founder alleles have been reported; all variants are private to individual families. Segregation analysis confirms autosomal dominant transmission with high penetrance (affected relatives: 8).

Functional analyses in heterologous expression systems demonstrate that AF-linked variants reduce gap junction conductance, impair trafficking to the plasma membrane, and accelerate proteasomal degradation. Some mutants (p.Gly38Asp, p.Ala96Ser) also exhibit gain-of-hemichannel function, increasing dye uptake in cell assays. Electrophysiological studies in rat atrial myocytes expressing p.Pro88Ser, p.Gly38Asp, or p.Ala96Ser reveal slowed conduction velocities and heightened AF inducibility, mirroring human phenotypes ([PMID:24973497], [PMID:24457199], [PMID:28457700]).

Integration of genetic segregation, absence in controls, and concordant functional data supports a strong clinical validity for the GJA5–familial atrial fibrillation association. The pathogenic mechanism involves haploinsufficiency and dominant-negative effects on gap junction assembly, with some alleles also conferring aberrant hemichannel activity. These insights enable more accurate variant interpretation and inform precision management strategies for familial AF.

Key Take-home: Autosomal dominant GJA5 variants causing impaired gap junction coupling or gain-of-hemichannel function are clinically actionable markers for familial atrial fibrillation risk and guide diagnostic and therapeutic decision-making.

References

• Europace • 2010 • Novel connexin40 missense mutations in patients with familial atrial fibrillation. [PMID:20650941]
• Human mutation • 2013 • Novel germline GJA5/connexin40 mutations associated with lone atrial fibrillation impair gap junctional intercellular communication. [PMID:23348765]
• Disease models & mechanisms • 2014 • An atrial-fibrillation-linked connexin40 mutant is retained in the endoplasmic reticulum and impairs the function of atrial gap-junction channels. [PMID:24626989]
• FEBS letters • 2014 • Atrial fibrillation-associated connexin40 mutants make hemichannels and synergistically form gap junction channels with novel properties. [PMID:24457199]
• Journal of molecular and cellular cardiology • 2014 • Degradation of a connexin40 mutant linked to atrial fibrillation is accelerated. [PMID:24973497]
• Heart, lung & circulation • 2018 • Human Connexin40 Mutations Slow Conduction and Increase Propensity for Atrial Fibrillation. [PMID:28457700]

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