先天性Q—T间期延长综合征3型-家系基因突变分析

Gene mutation analysis of a Chinese family of congenital long Q-T syndrome type three

目的 对一个表现有先天性Q-T间期延长综合征，同时表现有扩张性心肌病、心脏传导障碍性疾病的家系进行相关基闪分析，探讨其发病机制。方法一个中国人3代多表现型的先天性Q—T间期延长综合征家系，采集8名家系成员和100名健康对照血样，采用PCR扩增、DNA直接测序技术进行SCN5A、KCNQI、KCNH2、LAMINA／C基因突变分析，采用多聚酶链反应——单链构象多态性进行基因型和表型研究。结果PCR-DNA直接测序在先证者钠通道SCN5A基因第26号外显子发现了9个碱基CAGAAGCCC缺失突变，该突变位于SCN5A基因DⅢ和DⅣ连接区域，导致第1507位谷氨酰胺、第1508位赖氨酸、第1509位脯氨酸3个氨基酸缺失。家系中患者检出与先证者棚同的突变，而家系内参加本研究的健康人和家系外100名健康对照未出现这种突变。结论SCN5A基因突变是部分先犬性Q—T间期延长综合征的分子发病机制，SCN5A基阂delQKP1507—1509突变是国内未曾报道过的新突变，国外的相同突变报道仪表现为Q—T间期延长综合征，无其他表型。进一步开展SCN5A delQKP1507—1509突变的功能研究有助于珲解棚关疾病的分子发病机制。

Objective 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 ventficular 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. Methods 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 SCNSA gene for mutation analysis. Polymerase chain reaction-single strand conformation polymorphism （PCR-SSCP） was used to exclude polymorphism. Results 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 Glnl507-LyslS08-Prol509 （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. Conclusion The result of the present study suggests that SCN5A mutation delQKP1507-1509 exists in patients with LQTs. The delQKPI507-1509 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.