Shi Rui-ming, Ma Ai-qun, Zhang Yan-min, Yang Chun, Huang Chen, Zhou Xi-hui, Liu Xiao-hong
Department of Pediatrics, First Affiliated Hospital, Cardiovascular Ion Channel Disease Laboratory of Medical College of Xi'an Jiaotong University, Xi'an 710061, China.
Zhonghua Er Ke Za Zhi. 2009 Dec;47(12):926-30.
The congenital long QT syndrome (LQTs) is a hereditary disorder in which most affected family members have delayed ventricular repolarization manifested on the electrocardiogram (ECG) as QT interval prolongation. The disorder is associated with an increased propensity to arrhythmogenic syncope, polymorphous ventricular tachycardia (torsade de pointes), and sudden arrhythmic death. LQTs is due to mutations involving principally the myocyte ion-channels, and this monogenetic disorder has an autosomal inheritance pattern. This study investigated the gene mutation of a Chinese family of LQTs with multiple phenotypes including dilated cardiomyopathy (DCM) and cardiac conduction defects, thus to understand the molecular pathogenesis of the diseases.
A three-generation Chinese LQTs family with multiple phenotypes was investigated. Blood sample was collected from the 8 family members and 100 unassociated normal individuals. Polymerase chain reaction (PCR)-DNA direct sequencing was performed to screen all exons and their flanking introns of SCN5A gene for mutation analysis. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to exclude polymorphism.
PCR amplification and subsequent direct sequencing of SCN5A from proband revealed a heterozygous deletion of nine base pairs (CAGAAGCCC) in exon 26, corresponding to the three amino acid residues Gln1507-Lys1508-Pro1509 (QKP). This mutation is localized in the linker region between DIII-DIV of SCN5A. The same mutation was found in another patient (her grandmother) and excluded in the remaining living subjects in this family. This mutation was confirmed using SSCP in 100 unassociated healthy individuals. Similar analysis excluded possible mutations that would lead to amino acid changes in KCNQ1, KCNH2 and LAMIN A/C commonly associated with LQTs and DCM with conduction disorders, no new mutations that would lead to amino acid changes was found.
The result of the present study suggests that SCN5A mutation delQKP1507-1509 exists in patients with LQTs. The delQKP1507-1509 of SCN5A is a novel mutation in Chinese people. The same mutation was previously reported in a French family with only a single LQTs phenotype. Further studies on functional expression of SCN5A mutation delQKP1507-1509 will be helpful to understand the mechanism of the multiple phenotypes.
先天性长QT综合征（LQTs）是一种遗传性疾病，大多数受累家庭成员存在心室复极延迟，在心电图（ECG）上表现为QT间期延长。该疾病与致心律失常性晕厥、多形性室性心动过速（尖端扭转型室速）及心律失常性猝死的倾向增加有关。LQTs主要是由于涉及心肌细胞离子通道的突变引起，这种单基因疾病具有常染色体遗传模式。本研究调查了一个具有包括扩张型心肌病（DCM）和心脏传导缺陷等多种表型的中国LQTs家系的基因突变情况，以了解这些疾病的分子发病机制。
对一个具有多种表型的三代中国LQTs家系进行调查。采集了8名家系成员和100名无关正常个体的血样。采用聚合酶链反应（PCR）-DNA直接测序法对SCN5A基因的所有外显子及其侧翼内含子进行突变分析。采用聚合酶链反应-单链构象多态性（PCR-SSCP）法排除多态性。
对先证者的SCN5A进行PCR扩增及后续直接测序，发现外显子26有9个碱基对（CAGAAGCCC）的杂合缺失，对应三个氨基酸残基Gln1507-Lys1508-Pro1509（QKP）。该突变位于SCN5A的DIII-DIV之间的连接区。在另一名患者（其祖母）中发现了相同的突变，该家系中其余在世个体未检测到该突变。在100名无关健康个体中采用SSCP法证实了该突变。类似分析排除了可能导致与LQTs及伴有传导障碍的DCM常见相关的KCNQ1、KCNH2和Lamin A/C中氨基酸改变的突变，未发现会导致氨基酸改变的新突变。
本研究结果提示，LQTs患者中存在SCN5A突变delQKP1507-1509。SCN5A的delQKP1507-1509在中国人群中是一种新的突变。此前在一个仅具有单一LQTs表型的法国家系中报道过相同的突变。对SCN5A突变delQKP1507-1509的功能表达进行进一步研究将有助于理解多种表型的机制。
