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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease
Circulation: Cardiovascular Genetics, Volume 3, No. 4, Year 2010
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Description
Background-Isolated cardiac conduction block is a relatively common condition in young and elderly populations. Genetic predisposing factors have long been suspected because of numerous familial case reports. Deciphering genetic predisposing factors of conduction blocks may give a hint at stratifying conduction block carriers in a more efficient way. Methods and Results-One Lebanese family and 2 French families with autosomal dominant isolated cardiac conduction blocks were used for linkage analysis. A maximum combined multipoint lod score of 10.5 was obtained on a genomic interval including more than 300 genes. After screening 12 genes of this interval for mutation, we found a heterozygous missense mutation of the TRPM4 gene in each family (p.Arg164Trp, p.Ala432Thr, and p.Gly844Asp). This gene encodes the TRPM4 channel, a calcium-activated nonselective cation channel of the transient receptor potential melastatin (TRPM) ion channel family. All 3 mutations result in an increased current density. This gain of function is due to an elevated TRPM4 channel density at the cell surface secondary to impaired endocytosis and deregulation of Small Ubiquitin MOdifier conjugation (SUMOylation). Furthermore, we showed by immunohistochemistry that TRPM4 channel signal level is higher in atrial cardiomyocytes than in common ventricular cells, but is highest in Purkinje fibers. Small bundles of highly TRPM4-positive cells were found in the subendocardium and in rare intramural bundles. Conclusions-the TRPM4 gene is a causative gene in isolated cardiac conduction disease with mutations resulting in a gain of function and TRPM4 channel being highly expressed in cardiac Purkinje fibers. © 2010 American Heart Association, Inc.
Authors & Co-Authors
Liu, Hui
France, Lyon
Université de Lyon
France, Lyon
Chu de Lyon
Zein, Loubna El
France, Lyon
Université de Lyon
France, Lyon
Chu de Lyon
Kruse, Martin
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Guinamard, Romain
France, Caen
Université de Caen Normandie
Beckmann, Alf
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
France, Lyon
Chu de Lyon
Bozio, André
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
France, Lyon
Chu de Lyon
Kurtbay, Güven
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Megarbane, Andre
Lebanon, Beirut
Université Saint-joseph de Beyrouth
Ohmert, Iris
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Blaysat, Gérard
France, La Tronche
Hôpital A. Michallon Chu Grenoble
Villain, Elisabeth
France, Paris
Hôpital Necker Enfants Malades
Pongs, Olaf
Germany, Hamburg
Universitätsklinikum Hamburg-eppendorf
Bouvagnet, Patrice
France, Lyon
Université de Lyon
France, Lyon
Chu de Lyon
Statistics
Citations: 200
Authors: 13
Affiliations: 7
Identifiers
Doi:
10.1161/CIRCGENETICS.109.930867
ISSN:
1942325X
e-ISSN:
19423268
Research Areas
Cancer
Genetics And Genomics
Noncommunicable Diseases