van den Berg M H, Wilde A A, Robles de Medina E O, Meyer H, Geelen J L, Jongbloed R J, Wellens H J, Geraedts J P
Division of Genetics, University Maastricht, The Netherlands.
Hum Genet. 1997 Sep;100(3-4):356-61. doi: 10.1007/s004390050516.
The Romano Ward long QT syndrome (LQTS) has an autosomal dominant mode of inheritance. Patients suffer from syncopal attacks often resulting in sudden cardiac death. The main diagnostic parameter is a prolonged QT(c) interval as judged by electro-cardiographic investigation. LQTS is a genetically heterogeneous disease with four loci having been identified to date: chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3) and 4q25-26 (LQT4). The corresponding genes code for potassium channels KVLQT1 (LQT1) and HERG (LQT2) and the sodium channel SCN5A (LQT3). The KVLQT1 gene is characterized by six transmembrane domains (S1-S6), a pore region situated between the S5 and S6 domains and a C-terminal domain accounting for approximately 60% of the channel. This domain is thought to be co-associated with another protein, viz. minK (minimal potassium channel). We have studied a Romano Ward family with several affected individuals showing a severe LQTS phenotype (syncopes and occurrence of sudden death). Most affected individuals had considerable prolongations of QT(c). By using haplotyping with a set of markers covering the four LQT loci, strong linkage was established to the LQT1 locus, whereas the other loci (LQT2, LQT3 and LQT4) could be excluded. Single-strand conformation polymorphism analysis and direct sequencing were used to screen the KVLQT1 gene for mutations in the S1-S6 region, including the pore domain. We identified a Gly-216-Arg substitution in the S6 transmembrane domain of KVLQT1. The mutation was present in all affected family members but absent in normal control individuals, providing evidence that the mutated KVLQT1-gene product indeed caused LQTS in this family. The mutated KVLQT1-gene product thus probably results in a dominant negative suppression of channel activity.
罗曼诺-沃德长QT综合征（LQTS）呈常染色体显性遗传模式。患者会出现晕厥发作，常导致心源性猝死。主要诊断参数是通过心电图检查判断QT（c）间期延长。LQTS是一种基因异质性疾病，迄今已确定了四个位点：染色体11p15.5（LQT1）、7q35 - 36（LQT2）、3p21 - 24（LQT3）和4q25 - 26（LQT4）。相应的基因编码钾通道KVLQT1（LQT1）、HERG（LQT2）和钠通道SCN5A（LQT3）。KVLQT1基因的特征是具有六个跨膜结构域（S1 - S6）、位于S5和S6结构域之间的孔区以及占通道约60%的C末端结构域。该结构域被认为与另一种蛋白质即minK（最小钾通道）共同相关。我们研究了一个罗曼诺-沃德家族，其中有几个受影响的个体表现出严重的LQTS表型（晕厥和猝死发生）。大多数受影响个体的QT（c）有显著延长。通过使用覆盖四个LQT位点的一组标记进行单倍型分析，确定与LQT1位点有强连锁关系，而其他位点（LQT2、LQT3和LQT4）可被排除。采用单链构象多态性分析和直接测序来筛查KVLQT1基因S1 - S6区域（包括孔结构域）的突变。我们在KVLQT1的S6跨膜结构域中鉴定出一个甘氨酸216 - 精氨酸替代。该突变存在于所有受影响的家庭成员中，但在正常对照个体中不存在，这证明突变的KVLQT1基因产物确实导致了该家族的LQTS。因此，突变的KVLQT1基因产物可能导致通道活性的显性负性抑制。
