T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss—apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.

中文翻译：

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与癫痫和听力损失相关的 Cav3.2 钙通道错义变异的电生理学特征

T型钙通道病包括一组由编码不同T型钙通道的基因突变引起或加剧的人类疾病。最近，在一名患有癫痫和听力损失的患者中报道了编码 Cav3.2 T 型钙通道的 CACNA1H 基因中的新杂合错义突变，这显然是第一个与感音神经性听力状况相关的 CACNA1H 突变。该突变导致 Cav3.2 的第二跨膜螺旋的近胞外端第 132 位的精氨酸被组氨酸 (R132H) 取代。在这项研究中，我们使用 tsA-201 细胞的全细胞膜片钳记录报告了这种新变体的电生理学特征。我们的数据揭示了通道的微小门控改变，表现为 T 型电流密度的轻微增加和从失活中恢复较慢，以及通道对外部 pH 变化的敏感性增强。R132H 突变引起的这些生物物理变化和 pH 敏感性改变在多大程度上导致观察到的致病性仍然是一个悬而未决的问题，这将需要分析与相同病理相关的其他 CACNA1H 变体。