Hum Mutat 2000 Jan 01;155:483. doi: 10.1002/(SICI)1098-1004(200005)15:5<483::AID-HUMU18>3.0.CO;2-T.

Analysis of the human KCNH2(HERG) gene: identification and characterization of a novel mutation Y667X associated with long QT syndrome and a non-pathological 9 bp insertion.

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Long QT (LQT) syndrome is a potentially life-threatening disorder, characterized by a distinct cardiac arrhythmia known as torsades de pointes. Mutations within a number of genes linked to the familial form, including that coding for a cardiac potassium channel called KCNH2 (HERG), have been described based on the characterized genomic organization. A standardized method was developed to screen the entire gene for gene variants. We report a single base pair substitution, introducing a premature STOP codon at codon 667 of the gene in a healthy individual with an extended QTc interval (460 msec). In vitro expression of the codon Y667X variant in Xenopus oocyte suggests that the autosomal dominant variant does not function in a dominant/negative manner and cannot co-assemble to form a channel, resulting in a reduction of the KCNH2 current, and an extension of the QT interval. This indicates that pathogenic LQT gene variants exist in the apparently normal population, the prognosis and clinical consequences of which remain to be determined. The assays described should facilitate future studies into this area.

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Species referenced: Xenopus laevis
Genes referenced: arfgap1 kcnh2