Dataset Information

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

ABSTRACT:

Background

Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phenotype correlation for that mutation.

Methods and results

We screened 156 probands with PFHBI. In addition to 12 sodium channel mutations, we found a germ line GJA5 (connexin40 [Cx40]) mutation (Q58L) in 1 family. Heterologous expression of Cx40-Q58L in connexin-deficient neuroblastoma cells resulted in marked reduction of junctional conductance (Cx40-wild type [WT], 22.2±1.7 nS, n=14; Cx40-Q58L, 0.56±0.34 nS, n=14; P<0.001) and diffuse localization of immunoreactive proteins in the vicinity of the plasma membrane without formation of gap junctions. Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in ≈50% of cells; well-defined gap junctions were observed in other cells. Junctional conductance values correlated with the distribution of gap junction plaques.

Conclusions

Mutation Cx40-Q58L impairs gap junction formation at cell-cell interfaces. This is the first demonstration of a germ line mutation in a connexin gene that associates with inherited ventricular arrhythmias and emphasizes the importance of Cx40 in normal propagation in the specialized conduction system.

SUBMITTER: Makita N

PROVIDER: S-EPMC4274644 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Makita Naomasa N Seki Akiko A Sumitomo Naokata N Chkourko Halina H Fukuhara Shigetomo S Watanabe Hiroshi H Shimizu Wataru W Bezzina Connie R CR Hasdemir Can C Mugishima Hideo H Makiyama Takeru T Baruteau Alban A Baron Estelle E Horie Minoru M Hagiwara Nobuhisa N Wilde Arthur A M AA Probst Vincent V Le Marec Hervé H Roden Dan M DM Mochizuki Naoki N Schott Jean-Jacques JJ Delmar Mario M

Circulation. Arrhythmia and electrophysiology 20120113 1

<h4>Background</h4>Progressive familial heart block type I (PFHBI) is a hereditary arrhythmia characterized by progressive conduction disturbances in the His-Purkinje system. PFHBI has been linked to genes such as SCN5A that influence cardiac excitability but not to genes that influence cell-to-cell communication. Our goal was to explore whether nucleotide substitutions in genes coding for connexin proteins would associate with clinical cases of PFHBI and if so, to establish a genotype-cell phen ...[more]

PMID: 22247482

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Dataset Information

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

Background

Methods and results

Conclusions

Publications

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

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