Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstr. 1-2, 35037 Marburg, Germany.
Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Domagkstr. 3, 48149 Münster, Germany.
J Mol Cell Cardiol. 2015 Mar;80:186-95. doi: 10.1016/j.yjmcc.2015.01.002. Epub 2015 Jan 26.
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.
CACNA1C 基因编码 L 型钙通道 Cav1.2，其功能获得性突变可导致 Timothy 综合征（TS），这是一种多系统疾病，具有畸形特征、长 QT 综合征（LQTS）和自闭症谱系障碍。TS 患者存在位于可变剪接外显子 8 中的杂合性突变（G402S 和 G406R），通过失活的电压依赖性降低而导致功能获得性。在对 540 名非综合征性 LQTS 患者进行筛查后，我们在通道的不同区域鉴定到了 6 种具有功能相关性的 CACNA1C 突变。所有这些突变导致的功能获得性结合了不同的机制，包括电流幅度、失活速率以及激活或失活的电压依赖性的改变，与 TS 相似。计算机模拟支持这样的理论，即新型 CACNA1C 突变可延长动作电位持续时间。我们得出结论，基因型阴性的 LQTS 患者应调查 CACNA1C 中的突变，因为 Cav1.2 的功能获得性可能导致 LQTS，只有特定且罕见的突变（即外显子 8 中的突变）才会导致多系统的 TS。
