Striessnig Jörg
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
Front Synaptic Neurosci. 2021 Mar 3;13:634760. doi: 10.3389/fnsyn.2021.634760. eCollection 2021.
This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca channels. Ca channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca-channelopathies with existing or novel Ca-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.
本综述总结了我们目前对电压门控钙通道家族中与人类疾病相关的基因变异的认识。钙通道病涵盖了广泛的疾病，包括癫痫、自闭症谱系障碍、智力残疾、发育迟缓、小脑共济失调和变性、严重心律失常、心源性猝死、眼病以及内分泌疾病，如先天性高胰岛素血症和醛固酮增多症。特别关注的是，在对明确的患者队列进行下一代测序研究时，在形成孔道的α1亚基中发现的错义突变数量迅速增加。与可能破坏基因的突变不同，这些突变不仅会导致通道功能丧失，还会诱导典型的功能变化，从而增强通道活性和钙信号传导。这种功能获得性突变可能代表了使用现有或新型钙通道抑制剂对钙通道病进行突变特异性治疗的靶点。此外，许多致病突变影响电压感受器中的正电荷，有可能通过电压感受器形成门控孔电流。如果在功能研究中得到证实，门控孔电流的特异性阻滞剂也可能具有治疗意义。
