Voltage-Gated Ca(2+)-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function - Implications for Potential Therapies.
Voltage-Gated Ca(2+)-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function - Implications for Potential Therapies.
复制标题
电压门控Ca（2+）通道α1亚基新生错义突变：功能的获得或丧失-潜在治疗的意义。
DOI：
10.3389/fnsyn.2021.634760
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发表时间：
2021
影响因子：
3.7
通讯作者：
Striessnig J
中科院分区：
文献类型：
--
作者：
Striessnig J
这篇综述总结了我们目前对电压门控 Ca2+ 通道家族中与人类疾病相关的遗传变异的了解。 Ca2+通道病涵盖多种疾病，包括癫痫、自闭症谱系障碍、智力障碍、发育迟缓、小脑共济失调和变性、严重心律失常、心源性猝死、眼部疾病和内分泌失调（如先天性胰岛素增多症和醛固酮增多症）。特别关注的是通过对明确的患者群体进行下一代测序研究，在成孔 α1 亚基中发现的从头错义突变数量迅速增加。与可能的基因破坏突变相比，这些突变不仅会导致通道功能丧失，而且还可以诱导典型的功能变化，从而增强通道活性和 Ca2+ 信号传导。这种功能获得性突变可以代表使用现有或新型 Ca2+ 通道抑制剂对 Ca2+ 通道病进行突变特异性治疗的治疗靶点。此外，许多致病突变会影响电压传感器中的正电荷，有可能通过电压传感器形成门控孔电流。如果在功能研究中得到证实，门控孔电流的特定阻断剂也可能具有治疗意义。
This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ 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 de novo 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 Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-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.
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影响因子：
5.5
作者：
Burashnikov, Elena;Pfeiffer, Ryan;Barajas-Martinez, Hector;Delpon, Eva;Hu, Dan;Desai, Mayurika;Borggrefe, Martin;Haeissaguerre, Michel;Kanter, Ronald;Pollevick, Guido D.;Guerchicoff, Alejandra;Laino, Ruben;Marieb, Mark;Nademanee, Koonlawee;Nam, Gi-Byoung;Robles, Roberto;Schimpf, Rainer;Stapleton, Dwight D.;Viskin, Sami;Winters, Stephen;Wolpert, Christian;Zimmern, Samuel;Veltmann, Christian;Antzelevitch, Charles
通讯作者：
Antzelevitch, Charles
影响因子：
2
作者：
Carreno, Oriel;Corominas, Roser;Cormand, Bru
通讯作者：
Cormand, Bru
影响因子：
2.7
作者：
Ben-Johny M;Dick IE;Sang L;Limpitikul WB;Kang PW;Niu J;Banerjee R;Yang W;Babich JS;Issa JB;Lee SR;Namkung H;Li J;Zhang M;Yang PS;Bazzazi H;Adams PJ;Joshi-Mukherjee R;Yue DN;Yue DT
通讯作者：
Yue DT
影响因子：
3.8
作者：
Barresi, Sabina;Dentici, Maria Lisa;Tartaglia, Marco
通讯作者：
Tartaglia, Marco
影响因子：
30.8
作者：
Azizan, Elena A. B.;Poulsen, Hanne;Brown, Morris J.
通讯作者：
Brown, Morris J.