title: An atrial-fibrillation-linked connexin40 mutant is retained in the endoplasmic reticulum and impairs the function of atrial gap-junction channels.
abstract: Connexin40 (Cx40)-containing gap-junction channels are expressed in the atrial myocardium and provide a low-resistance passage for rapid impulse propagation. A germline mutation in the GJA5 gene, which encodes Cx40, resulting in a truncated Cx40 (Q49X) was identified in a large Chinese family with lone (idiopathic) atrial fibrillation (AF). This mutation co-segregated with seven AF probands in an autosomal-dominant way over generations. To test the hypothesis that this Cx40 mutant affects the distribution and function of atrial gap junctions, we studied the Q49X mutant in gap-junction-deficient HeLa and N2A cells. The Q49X mutant, unlike wild-type Cx40, was typically localized in the cytoplasm and failed to form gap-junction plaques at cell-cell interfaces. When the Q49X mutant was co-expressed with Cx40 or Cx43, the mutant substantially reduced the gap-junction plaque formation of Cx40 and Cx43. Electrophysiological studies revealed no electrical coupling of cell pairs expressing the mutant alone and a significant decrease in the coupling conductance when the mutant was co-expressed with Cx40 or Cx43. Further colocalization experiments with the organelle residential proteins indicate that Q49X was retained in the endoplasmic reticulum. These findings provide evidence that the Q49X mutant is capable of impairing gap-junction distribution and function of key atrial connexins, which might play a role in the predisposition to and onset of AF.
authors.affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, ON N6A 5C1, Canada.
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Tong
authors.forename: Honghong
authors.initials: H
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.forename: Weixiong
authors.initials: W
authors.lastname: Huang
authors.forename: Dale W
authors.initials: DW
authors.lastname: Laird
authors.forename: Donglin
authors.initials: D
authors.lastname: Bai
mesh_terms: D000328:Adult; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D017629:Gap Junctions / Q000378:metabolism*; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D000097003:Gap Junction alpha-5 Protein
chemical_list: D018031:Connexin 43; D017630:Connexins; D008164:Luminescent Proteins; D050505:Mutant Proteins; D000097003:Gap Junction alpha-5 Protein; C413663:fluorescent protein 583
keywords: Atrial fibrillation; Connexin40; Gap junctions; Genetics; Germline mutation