title: Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease.
abstract: 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.
  
  
  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.
authors.affiliation: Université de Lyon, Laboratoire Cardiogénétique, Equipe d'Accueil 4171, Lyon, France.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Loubna
authors.initials: L
authors.lastname: El Zein
authors.forename: Martin
authors.initials: M
authors.lastname: Kruse
authors.forename: Romain
authors.initials: R
authors.lastname: Guinamard
authors.forename: Alf
authors.initials: A
authors.lastname: Beckmann
authors.forename: André
authors.initials: A
authors.lastname: Bozio
authors.forename: Güven
authors.initials: G
authors.lastname: Kurtbay
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Iris
authors.initials: I
authors.lastname: Ohmert
authors.forename: Gérard
authors.initials: G
authors.lastname: Blaysat
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Villain
authors.forename: Olaf
authors.initials: O
authors.lastname: Pongs
authors.forename: Patrice
authors.initials: P
authors.lastname: Bouvagnet
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D000075224:Cardiac Conduction System Disease; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005190:Family; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006327:Heart Block / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014162:Transfection
chemical_list: D050053:TRPM Cation Channels; C437888:TRPM4 protein, human