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Functional Characterization of Novel Atrial Fibrillation-Linked GJA5 (Cx40) Mutants

Mahmoud Noureldin1, Honghong Chen2, Donglin Bai3

  • 1Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1 Canada. mnourel@uwo.ca.

International Journal of Molecular Sciences
|March 29, 2018
PubMed

Insights

Four new connexin 40 (Cx40) mutations were found in atrial fibrillation (AF) patients. The Q236H mutation significantly reduced gap junction function, potentially contributing to AF development.

Area of Science:

  • Cardiovascular Research
  • Molecular Biology
  • Genetics

Background:

  • Atrial fibrillation (AF) is a prevalent cardiac arrhythmia.
  • Connexin 40 (Cx40) mutations are implicated in cardiac arrhythmias.
  • Four novel heterozygous Cx40 mutations (K107R, L223M, Q236H, I257L) were identified in AF patients.

Purpose of the Study:

  • To investigate the functional consequences of novel Cx40 mutations.
  • To assess the cellular localization and gap junction (GJ) function of Cx40 mutants.
  • To determine if Cx40 mutations contribute to AF pathogenesis.

Main Methods:

  • Expression of GFP-tagged and untagged Cx40 mutants in connexin-deficient cells.
  • Analysis of Cx40 mutant localization at cell-cell junctions.
  • Measurement of GJ coupling conductance (Gj) and transjunctional voltage-dependent gating (Vj gating).

Main Results:

  • All four Cx40 mutants localized to cell-cell junctions, similar to wildtype Cx40.
  • The Cx40 Q236H mutant, but not others, significantly reduced GJ coupling conductance (Gj).
  • Co-expression of Cx40 Q236H with Cx43 also decreased Gj.
  • Altered Vj gating properties were observed for GJs formed by Cx40 Q236H.

Conclusions:

  • The Cx40 Q236H mutation impairs GJ function and alters gating properties.
  • Reduced GJ function and altered gating associated with Cx40 Q236H may promote AF.
  • These findings highlight the role of Cx40 mutations in AF pathophysiology.

Keywords:
Vj gatingatrial fibrillationconnexin40gap junction channelpatch clamp

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