Identification and functional characterization of KCNQ1 mutations around the exon 7–intron 7 junction affecting the splicing process

DOI Web Site Web Site PubMed 被引用文献10件 参考文献28件 オープンアクセス

説明

KCNQ1 gene encodes the delayed rectifier K(+) channel in cardiac muscle, and its mutations cause long QT syndrome type 1 (LQT1). Especially exercise-related cardiac events predominate in LQT1. We previously reported that a KCNQ1 splicing mutation displays LQT1 phenotypes.We identified novel mutation at the third base of intron 7 (IVS7 +3AG) in exercise-induced LQT1 patients. Minigene assay in COS7 cells and RT-PCR analysis of patients' lymphocytes demonstrated the presence of exon 7-deficient mRNA in IVS7 +3AG, as well as c.1032GA, but not in c.1022CT. Real-time RT-PCR demonstrated that both IVS7 +3AG and c.1032GA carrier expressed significant amounts of exon-skipping mRNAs (18.8% and 44.8% of total KCNQ1 mRNA). Current recordings from Xenopus oocytes injected cRNA by simulating its ratios of exon skipping displayed a significant reduction in currents to 64.8 ± 4.5% for IVS7 +3AG and to 41.4 ± 9.5% for c.1032GA carrier, respectively, compared to the condition without splicing error. Computer simulation incorporating these quantitative results revealed the pronounced QT prolongation under beta-adrenergic stimulation in IVS7 +3AG carrier model.Here we report a novel splicing mutation IVS7 +3AG, identified in a family with mild form LQT1 phenotypes, and examined functional outcome in comparison with three other variants around the exon 7-intron 7 junction. In addition to c.1032GA mutation, IVS7 +3AG generates exon-skipping mRNAs, and thereby causing LQT1 phenotype. The severity of clinical phenotypes appeared to differ between the two splicing-related mutations and to result from the amount of resultant mRNAs and their functional consequences.

収録刊行物

被引用文献 (10)*注記

もっと見る

参考文献 (28)*注記

もっと見る

関連プロジェクト

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ