函数增益
长QT综合征
第1.2节
外显子
突变
自闭症谱系障碍
损失函数
遗传学
医学
内科学
钙通道
内分泌学
生物
自闭症
基因
钙
QT间期
表型
精神科
作者
Konstantin Wemhöner,Corinna Friedrich,Birgit Stallmeyer,Alison J. Coffey,Andrew A. Grace,Sven Zumhagen,Guiscard Seebohm,Beatriz Ortiz-Bonnin,Susanne Rinné,Frank B. Sachse,Eric Schulze-Bahr,Niels Decher
标识
DOI:10.1016/j.yjmcc.2015.01.002
摘要
Gain-of-function mutations in CACNA1C, encoding the L-type Ca(2+) channel Cav1.2, cause Timothy syndrome (TS), a multi-systemic disorder with dysmorphic features, long-QT syndrome (LQTS) and autism spectrum disorders. TS patients have heterozygous mutations (G402S and G406R) located in the alternatively spliced exon 8, causing a gain-of-function by reduced voltage-dependence of inactivation. Screening 540 unrelated patients with non-syndromic forms of LQTS, we identified six functional relevant CACNA1C mutations in different regions of the channel. All these mutations caused a gain-of-function combining different mechanisms, including changes in current amplitude, rate of inactivation and voltage-dependence of activation or inactivation, similar as in TS. Computer simulations support the theory that the novel CACNA1C mutations prolong action potential duration. We conclude that genotype-negative LQTS patients should be investigated for mutations in CACNA1C, as a gain-of-function in Cav1.2 is likely to cause LQTS and only specific and rare mutations, i.e. in exon 8, cause the multi-systemic TS.
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