A novel splice mutation of HERG in a Chinese family with long QT syndrome.
Congenital long QT syndrome (LQTS) is a genetically heterogeneous disease in which six ion-channel genes have been identified. The phenotype-genotype relationships of the HERG (human ether-a-go-go-related gene) mutations are not fully understood. The objective of this study is to identify the underlying genetic basis of a Chinese family with LQTS and to characterize the clinical manifestations properties of the mutation. Single strand conformation polymorphism (SSCP) analyses were conducted on DNA fragments amplified by polymerase chain reaction from five LQT-related genes. Aberrant conformers were analyzed by DNA sequencing. A novel splice mutation in C-terminus of HERG was identified in this Chinese LQTS family, leading to the deletion of 11-bp at the acceptor splice site of Exon9 [Exon9 IVS del (-12-->-2)]. The mutation might affect, through deficient splicing, the putative cyclic nucleotide binding domain (CNBD) of the HERG K(+) channel. This mutation resulted in a mildly affected phenotype. Only the proband had a history of syncopes, while the other three individuals with long QT interval had no symptoms. Two other mutation carriers displayed normal phenotype. No sudden death occurred in the family. The 4 affected individuals and the two silent mutation carriers were all heterozygous for the mutation. It is the first splice mutation of HERG reported in Chinese LQTS families. Clinical data suggest that the CNBD mutation may be less malignant than mutations occurring in the pore region and be partially dominant over wild-type function.
Shang
Yun-peng
YP
Department of Cardiovascular Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xie
Xu-dong
XD
Wang
Xing-xiang
XX
Chen
Jun-zhu
JZ
Zhu
Jian-hua
JH
Tao
Qian-min
QM
Zheng
Liang-rong
LR
D044466:Asian People; D004252:DNA Mutational Analysis / Q000379:methods; D004274:DNA, Recombinant / Q000235:genetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005190:Family; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D015994:Incidence; D008133:Long QT Syndrome / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D011110:Polymorphism, Genetic; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors
D004274:DNA, Recombinant; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human