Zhang Xianqin, Chen Shenghan, Zhang Li, Liu Mugen, Redfearn Sharon, Bryant Randall M, Oberti Carlos, Vincent G Michael, Wang Qing K
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
BMC Med Genet. 2008 Sep 23;9:87. doi: 10.1186/1471-2350-9-87.
KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS), an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype.
In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis.
LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P < 0.0001).
Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.
KCNQ1和KCNH2是导致长QT综合征（LQTS）的两个最常见的钾通道基因，长QT综合征是一种遗传性心律失常，其特征为QT间期延长，发生尖端扭转型室速和猝死的风险增加。为了研究该疾病的表现度，本研究旨在鉴定可改变LQTS表型的突变和常见变异。
在本研究中，对112个LQTS家系进行了调查。其中，对两个大型LQTS家系进行了连锁分析，使用跨越已知LQTS基因的标记来鉴定用于突变分析的特定基因。对KCNH2和KCNQ1的所有外显子及外显子-内含子边界进行测序以进行突变分析。
在112个家系中的8个家系中鉴定出与LQTS相关的突变。鉴定出两个新突变，即KCNQ1中的L187P和KCNH2中的2020insAG。此外，在另一个LQTS家系中，我们发现KCNH2突变A490T与KCNH2中的一个常见单核苷酸多态性（SNP）K897T共分离。据报道，KCNH2 SNP K897T对QTc有修饰作用，但它是带来风险还是具有保护作用仍存在争议。值得注意的是，我们发现SNP K897T与突变A490T以顺式方向相互作用。与携带A490T或A490P的个体相比，7名携带A490T以及SNP K897T次要等位基因T的个体的QTc更短，症状更少（P < 0.000）。
我们基于家系的研究方法支持KCNH2 SNP K897T对LQTS患者具有保护作用。我们的研究首次调查了SNP K897T对位于顺式方向的另一个KCNH2突变的影响。总之，我们的结果扩展了LQTS的突变和临床谱，并为决定与室性心动过速和猝死风险增加相关联的QT间期延长的因素提供了见解。
