Lee-Chen G J, Tai D Y, Chu C H, Teng Y N
Department of Biology, National Taiwan Normal University, Taipei, Taiwan.
J Formos Med Assoc. 1999 Sep;98(9):649-52.
Romano-Ward syndrome is an autosomal dominant long-QT syndrome (LQTS) that predisposes affected individuals to sudden death from tachyarrhythmias. We investigated the molecular basis of LQTS in a Taiwanese kindred. Clinical and genetic analyses revealed that a mutation was linked to the human ether-a-go-go-related gene (HERG). The coding sequences and exon-intron borders of HERG were amplified by means of polymerase chain reaction and subjected to single-strand conformation polymorphism (SSCP) analysis. An exon with an aberrant SSCP pattern was cloned and sequenced to study the molecular lesion. A C-->T transition in codon 614, leading to substitution of a valine for an alanine residue in the pore region of the HERG protein, was identified. Analysis with Bsp12861 endonuclease digestion showed the mutation to be present in all affected family members. Given that an unaffected paternal uncle had inherited the same allele from the grandfather as the proband's father, a de novo mutation had apparently occurred in the father and was transmitted to his offspring. In addition to offering presymptomatic genetic diagnosis, identification of the disease-causing mutation may suggest new therapeutic approaches for treatment and prevention of this cardiovascular disease.
Romano-Ward综合征是一种常染色体显性长QT综合征（LQTS），使受影响个体易因快速性心律失常而猝死。我们研究了一个台湾家族中LQTS的分子基础。临床和基因分析显示，一种突变与人类ether-a-go-go相关基因（HERG）有关。通过聚合酶链反应扩增HERG的编码序列和外显子-内含子边界，并进行单链构象多态性（SSCP）分析。克隆并测序具有异常SSCP模式的外显子，以研究分子病变。在密码子614处发现了一个C→T转换，导致HERG蛋白孔区的丙氨酸残基被缬氨酸取代。用Bsp12861内切酶消化分析表明，该突变存在于所有受影响的家庭成员中。鉴于一位未受影响的叔祖父从祖父那里继承了与先证者父亲相同的等位基因，显然父亲发生了一个新发突变并传递给了他的后代。除了提供症状前的基因诊断外，致病突变的鉴定可能为这种心血管疾病的治疗和预防提示新的治疗方法。
