Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

中文翻译：

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与肌萎缩性侧索硬化症相关的罕见CACNA1H变体会导致Cav3.2 T型通道活性完全丧失。

肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，其特征在于皮质，脑干和脊髓运动神经元的逐渐丧失，导致肌肉无力和死亡。先前的研究表明，编码Cav3.2钙通道的CACNA1H是ALS中的易感基因。在本研究中，通过一小部分ALS患者的全基因组测序鉴定了两个杂合的CACNA1H变体。这些变体使用膜片钳电生理学，生物化学分析和分子模型进行功能表征。先前未报道的c.454GTAC> G变体在Cav3.2中造成高度保守的异亮氨酸残基的框内缺失（p.ΔI153），并导致通道功能完全丧失，对Cav3.2的显性负效应反式表达野生型通道。相反，c.3629C> T变体导致脯氨酸被亮氨酸（p.P1210L）错义取代，并产生了相对轻度的Cav3.2通道活性改变。新发现的ΔI153变体是第一个被报道导致Cav3.2通道功能完全丧失的报道。这些发现增加了这样的观念，即与罕见的CACNA1H变体相关的Cav3.2通道功能丧失可能是ALS复杂病因的危险因素。