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A connexin40 mutation associated with a malignant variant of progressive familial heart block type I

Naomasa Makita1, Akiko Seki, Naokata Sumitomo

  • 1Department of Molecular Pathophysiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. makitan@nagasaki-u.ac.jp

Circulation. Arrhythmia and Electrophysiology
|January 17, 2012
PubMed

Insights

A novel connexin40 (Cx40) mutation, Q58L, is linked to progressive familial heart block type I (PFHBI). This mutation impairs gap junction formation, highlighting Cx40's role in inherited arrhythmias.

Area of Science:

  • Genetics
  • Cardiology
  • Cell Biology

Background:

  • Progressive familial heart block type I (PFHBI) involves hereditary conduction disturbances.
  • Previous research linked PFHBI to cardiac excitability genes but not cell communication genes.

Purpose of the Study:

  • Investigate associations between connexin gene mutations and PFHBI.
  • Establish genotype-cell phenotype correlations for identified mutations.

Main Methods:

  • Screened 156 PFHBI probands for mutations.
  • Performed heterologous expression of identified mutations in cell models.
  • Assessed junctional conductance and protein localization.

Main Results:

  • Identified a germ line GJA5 (connexin40 [Cx40]) mutation (Q58L) in one family.
  • Cx40-Q58L significantly reduced junctional conductance and impaired gap junction formation.
  • Observed altered protein distribution and reduced gap junction plaque formation.

Conclusions:

  • The Cx40-Q58L mutation disrupts gap junction formation at cell interfaces.
  • This is the first demonstration of a connexin gene mutation causing inherited ventricular arrhythmias.
  • Emphasizes the critical role of Cx40 in the heart's specialized conduction system.
Abstract

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