TRPM4 non-selective cation channel variants in long QT syndrome

BMC Medical Genetics

Research Article

Jean-Jacques Schott¹  Vincent Probst²  Gilles Millat³  Hui Liu⁴  Patrice Bouvagnet⁵  Thomas Hof⁶  Laurent Sallé⁶  Romain Guinamard⁶  Corinne Ducreux⁷  Philippe Chevalier⁸ 

[1] Institut du thorax, INSERM UMR 1087, CNRS UMR 6291, Nantes, France;Institut du thorax, INSERM UMR 1087, CNRS UMR 6291, Nantes, France;Institut du thorax, Service de Cardiologie, CHU Nantes, Nantes, France;Laboratoire Cardiogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France;Laboratoire Cardiogénétique, Institut de Biologie et Chimie des Protéines, INSERM UMR 5305, Université Lyon 1, Lyon, France;Laboratoire Cardiogénétique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France;Present Address: Department of Anatomy, Hainan Medical College, 571101, Haikou, Hainan, China;Laboratoire Cardiogénétique, Institut de Biologie et Chimie des Protéines, INSERM UMR 5305, Université Lyon 1, Lyon, France;Laboratoire Cardiogénétique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France;Service de Cardiologie Pédiatrique, Hôpital Louis Pradel, Bron, France;Laboratoire Cardiogénétique, Groupe Hospitalier Est, 59 boulevard Pinel, CBPE, 69677, Bron, France;Normandie University, UNICAEN, EA 4650, Groupe Signalisation, Electrophysiologie et Imagerie des Lésions d’Ischémie-Reperfusion Myocardique, F-14032, Caen, France;Service de Cardiologie Pédiatrique, Hôpital Louis Pradel, Bron, France;Service de Cardiologie, Hôpital Louis Pradel, Bron, France;

关键词: Long QT syndrome;    TRPM4;    Electrophysiology;    Outward rectifying current;    Arrhythmia;    Gene mutation;   

DOI  :  10.1186/s12881-017-0397-4

 received in 2016-04-25, accepted in 2017-03-08,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundLong QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes.MethodsA cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4).ResultsFour TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current.ConclusionsThis study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4−/− mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.

【 授权许可】

CC BY   
© The Author(s). 2017