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Novel Germline GJA5 /Connexin40 Mutations Associated with Lone Atrial Fibrillation Impair Gap Junctional Intercellular Communication
Author(s) -
Sun Yiguo,
Yang YiQing,
Gong XiangQun,
Wang XinHua,
Li RuoGu,
Tan HongWei,
Liu Xu,
Fang WeiYi,
Bai Donglin
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22278
Subject(s) - gap junction , missense mutation , biology , proband , germline , genetics , germline mutation , mutant , mutation , gene , intracellular
Atrial fibrillation ( AF ) is the most common form of sustained cardiac arrhythmia worldwide. Here, we investigate the molecular and cellular mechanisms of lone AF ‐linked germline mutations in the connexin40 ( C x40) gene, GJA5 . The entire coding region of GJA5 was sequenced in 68 unrelated patients with lone AF . A novel germline heterozygous missense mutation in C x40 (p.I75 F ) was identified in one index patient. The mutation was also present in the proband's father with lone AF but was not found in the unaffected family members who were examined and 200 unrelated healthy control individuals. Electrophysiological studies revealed no electrical coupling of the cell pairs expressing the mutant alone and a significant reduction in gap junction coupling conductance when the mutant was coexpressed with wild‐type (wt) C x40 or C x43. Interestingly, another lone AF ‐linked C x40 mutant p. L 229 M did not show any apparent coupling defect when expressed alone or together with wt C x40 but specifically reduced the gap junction coupling when coexpressed with wt C x43. This study is the first to demonstrate that the germline familial mutations in C x40 impair the gap junctions through different mechanisms, which may predispose the mutant carriers to AF .