TRPM4 non-selective cation channel variants in long QT syndrome.
TRPM4 non-selective cation channel variants in long QT syndrome.
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长 QT 综合征中的 TRPM4 非选择性阳离子通道变异
DOI：
10.1186/s12881-017-0397-4
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发表时间：
2017-03-18
影响因子：
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通讯作者：
Bouvagnet P
中科院分区：
文献类型：
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作者：
Hof T;Liu H;Sallé L;Schott JJ;Ducreux C;Millat G;Chevalier P;Probst V;Guinamard R;Bouvagnet P
研究背景长QT综合征（LQTS）是一种以QT间期延长、晕厥和猝死为特征的遗传性心脏病。LQTS的致病基因很多，但并非所有的LQTS患者都有一个确定的突变，这表明LQTS的未知基因。（KCNQ 1、KCNH 2和SCN 5A），筛选瞬时潜在melastatin 4基因（TRPM 4）突变。（队列中的2.2%）被发现改变了高度保守的氨基酸，并且在对照群体中非常罕见或不存在。因此，这四个TRPM 4变异体被预测为致病的。此外，在这些TRPM 4变异携带者的DNA中，在13个主要长QT综合征基因中的任何一个中都没有发现突变。通过电生理学进一步研究了这些变体中的两个（p.Val441Met和p.Arg499Pro）。两种变异体均表现出典型的TRPM 4外向整流电流，但与野生型TRPM 4电流相比，该电流分别降低了61%和90%。结论本研究支持TRPM 4可解释一小部分LQTS患者的观点。TRPM 4对QT间期的贡献可能是多因素的，通过调节全细胞电流，但如Trpm 4 −/−小鼠所示，TRPM 4扩大了LQT基因的亚群（KCNJ 2在Andersen综合征和CACNA 1C在Timothy综合征），已知LQT基因通过比仅仅改变动作电位更复杂的多效性效应增加QT间期。
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, andSCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4).ResultsFourTRPM4variants (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 fourTRPM4variants 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 thatTRPM4 could account for a small percentage of LQTS patients.TRPM4contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4−/−mice, by modulating cardiomyocyte proliferation.TRPM4enlarges the subgroup of LQT genes (KCNJ2in Andersen syndrome andCACNA1Cin Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.