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.

• Authors: Naomasa Makita, Akiko Seki, Naokata Sumitomo, Halina Chkourko, Shigetomo Fukuhara, Hiroshi Watanabe, Wataru Shimizu, Connie R Bezzina, Can Hasdemir, Hideo Mugishima, Takeru Makiyama, Alban Baruteau, Estelle Baron, Minoru Horie, Nobuhisa Hagiwara, Arthur A M Wilde, Vincent Probst, Hervé Le Marec, Dan M Roden, Naoki Mochizuki, Jean-Jacques Schott, Mario Delmar
• Journal: Circulation. Arrhythmia and electrophysiology (Circ Arrhythm Electrophysiol) Vol. 5 Issue 1 Pg. 163-72 (Feb 2012) ISSN: 1941-3084 [Electronic] United States
• PMID: 22247482 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Connexins
• connexin 40
• DNA

Topics

• Biomarkers (metabolism)
• Blotting, Western
• Bundle of His (metabolism, physiopathology)
• Cardiac Conduction System Disease
• Child
• Connexins (genetics, metabolism)
• DNA (genetics)
• Electrocardiography
• Electrophysiologic Techniques, Cardiac
• Female
• Genetic Predisposition to Disease
• Heart Block (genetics, metabolism, physiopathology)
• Heart Rate
• Humans
• Immunohistochemistry
• Male
• Mutation
• Pedigree
• Polymerase Chain Reaction
• Prognosis