KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population

Abstract

The long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of the QT interval on electrocardiograms (ECGs), syncope and sudden death caused by a specific ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in ion channel genes including the cardiac sodium channel gene SCN5A, and potassium channel subunit genes KCNQ1, KCNH2, KCNE1, and KCNE2. Little information is available about LQTS mutations in the Chinese population. In this study, we characterized 42 Chinese LQTS families for mutations in the two most common LQTS genes, KCNQ1 and KCNH2. We report here the identification of four novel KCNQ1 mutations and three novel KCNH2 mutations. The KCNQ1 mutations include L191P in the S2-S3 cytoplasmic loop, F275S and S277L in the S5 transmembrane domain, and G306V in the channel pore. The KCNH2 mutations include L413P in transmembrane domain S1, E444D in the extracellular loop between S1 and S2, and L559H in domain S5. The location and character of these mutations expand the spectrum of KCNQ1 and KCNH2 mutations causing LQTS. Excitement, exercises, and stress appear to be the triggers for developing cardiac events (syncope, sudden death) for LQTS patients with KCNQ1 mutations F275S, S277L, and G306V, and all three KCNH2 mutations L413P, E444D and L559H. In contrast, cardiac events for an LQTS patient with KCNQ1 mutation L191P occurred during sleep or awakening from sleep. KCNH2 mutations L413P and L559H are associated with the bifid T waves on ECGs. Inderal or propanolol (a beta blocker) appears to be effective in preventing arrhythmias and syncope for an LQTS patient with the KCNQ1 L191P mutation.

Analysis of genetic and non-genetic factors that affect the QTc interval in a Mongolian population: the GENDISCAN study

“…Therefore, it is possible that there are other genes that regulate the QTc interval. Most previous studies focused on candidate regulation genes (Busjahn et al, 1999;Liu et al, 2002) already known as LQTS genes, but in order to identify unknown genes that regulate the QTc interval in the general population, a population-based whole genome study is necessary. An isolated population is appropriate for identifying genes that are responsible for complex traits because such a population reduces genetic heterogeneity and environmental diversity.…”

Genotype-based clinical manifestation and treatment of Chinese long QT syndrome patients withKCNQ1mutations – R380S and W305L

“…In order to better understand the genetic characteristics of Chinese type 1 long QT syndrome pedigrees, we reviewed all related published studies regarding genotype-phenotype correlations. [21][22][23][24][25][26][27][28][29] The corrected QT interval of all type 1 long QT syndrome probands ranged from 490 to 680 ms (568 ± 13 ms, n = 18). The longest corrected QT of 680 ms was reported in one proband with mutation S277L located in the S5 region of the Kv7.1 channel.…”

“…Of these C-terminal mutations, three probands suffered from recurrent syncope and two probands' family members had a history of syncope, consistent with our findings. Although some of those nine Chinese studies (e.g., Liu et al 22 ) revealed a family history of sudden cardiac death, none of them presented any proband with C-terminal mutation suffering sudden cardiac death finally, or with P-loop domain mutation who benefited from metoprolol. Our study, therefore, further filled a gap in the gene mutations database regarding Chinese type 1 long QT syndrome patients and might be of great benefit for the early prevention and development of individual therapeutics.…”

Site-directed mutagenesis of long QT syndrome KCNQ1 gene in vitro

“…In the previous studies, we firstly reported the LQTS mutation in the Chinese population and others continued to report on it [14,15]. But, the study of LQTS mutation function is the next step.…”