[中国先天性长QT综合征患者中的一种新型KCNQ1突变]

Liang Lu, Du Zhong-dong, Cai Ling-ling, Wu Jian-xin, Zheng Tong, Qi Tie-xiong

Capital Institute of Pediatrics, Beijing 100020, China.

Zhonghua Er Ke Za Zhi. 2003 Oct;41(10):724-7.

OBJECTIVE

Congenital long QT syndrome (LQTS) is an inherited disorder of cardiac repolarization characterized by prolongation of QT interval and polymorphic ventricular tachycardia torsade de pointes (TdP) in the electrocardiogram (ECG). Clinical symptoms include recurrent syncope, seizure or even sudden death. It is caused by mutations of at least seven genes, six of them encoding ion channels that determine the duration of ventricular action potentials. One of these genes, KCNQ1, encodes an alpha-subunit of cardiac slowly activated delayed rectifier potassium channel. Patients carrying mutations of KCNQ1 are named as LQT1, which accounts for 42% of patients with LQTS. This study sought to analyze the clinical data of Chinese with LQTS and to screen for the mutations of KCNQ1.

METHODS

The universally accepted phenotypic criteria of LQTS was used for identification of probands. There were six families with LQTS. They were enrolled in this study. Clinical and ECG data of each family member were recorded. Genomic DNA was prepared from peripheral blood lymphocytes. Polymerase chain reaction-single strand conformation polymorphism analysis was used to screen for mutations throughout the whole coding region of KCNQ1 and DNA sequencing was performed to determine the exact mutation site.

RESULTS

There were totally 13 patients in the six LQTS families. Five were male and eight female. One suffered from sudden death, 10 had syncope and 2 were asymptomatic. Eleven of the 13 patients had ECG data. Their QT and QTc (mean +/- SD) were (0.460 +/- 0.058) s and (0.516 +/- 0.058) s, respectively. TdP was observed in 3 patients (27%) during the syncope attack. By PCR-SSCP analysis, two novel KCNQ1 deletion mutations 356-357 Delta QQ and 626-631 Delta GSGGPP were identified in 7 patients of 2 families. None of 50 normal individuals carried these mutations, indicating these two mutations were likely to cause the disease. In addition, P448R was found in one affected and some unaffected members in other two families and in 7 of 50 (14%) normal individuals, indicating that this might be a polymorphism. All the three mutations located in C-terminal domain of KCNQ1 protein.

CONCLUSIONS

Two novel deletion mutations and one novel polymorphism of KCNQ1 gene were identified among 6 Chinese families with LQTS.

目的

先天性长QT综合征（LQTS）是一种遗传性心脏复极障碍疾病，其特征为心电图（ECG）中QT间期延长及多形性室性心动过速尖端扭转型室速（TdP）。临床症状包括反复发作的晕厥、癫痫甚至猝死。它由至少7个基因的突变引起，其中6个基因编码决定心室动作电位时程的离子通道。这些基因之一，KCNQ1，编码心脏缓慢激活延迟整流钾通道的α亚基。携带KCNQ1突变的患者被命名为LQT1，占LQTS患者的42%。本研究旨在分析中国LQTS患者的临床资料并筛查KCNQ1的突变。

方法

采用普遍接受的LQTS表型标准来识别先证者。有6个LQTS家系参与本研究。记录每个家庭成员的临床和ECG资料。从外周血淋巴细胞制备基因组DNA。采用聚合酶链反应-单链构象多态性分析筛查KCNQ1整个编码区的突变，并进行DNA测序以确定确切的突变位点。

结果

6个LQTS家系共有13例患者。5例男性，8例女性。1例猝死，10例有晕厥，2例无症状。13例患者中的11例有ECG资料。他们的QT和QTc（均值±标准差）分别为（0.460±0.058）秒和（0.516±0.058）秒。3例患者（27%）在晕厥发作时观察到TdP。通过PCR-SSCP分析，在2个家系的7例患者中鉴定出2种新的KCNQ1缺失突变356 - 357ΔQQ和626 - 631ΔGSGGPP。50名正常个体中均未携带这些突变，表明这两种突变可能致病。此外，在另外2个家系的1例患病和一些未患病成员以及50名正常个体中的7例（14%）中发现了P448R，表明这可能是一种多态性。所有3种突变均位于KCNQ1蛋白的C末端结构域。