A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

0522971 - ÚOCHB 2021 RIV GB eng J - Journal Article
Stringer, Robin Nicholas - Jurkovicova-Tarabova, B. - Huang, S. - Haji-Ghassemi, O. - Idoux, R. - Liashenko, A. - Souza, I. A. - Rzhepetskyy, Yuriy - Lacinová, L. - Van Petegem, F. - Zamponi, G. W. - Pamphlett, R. - Weiss, Norbert
A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity.
Molecular Brain. Roč. 13, Mar 6 (2020), č. článku 33. E-ISSN 1756-6606
Institutional support: RVO:61388963
Keywords : ALS * amyotrophic lateral sclerosis * motor neuron disease * CACNA1H * mutation * calcium channel * Cav3.2 channel * T-type channel * biophysics
OECD category: Biochemistry and molecular biology
Impact factor: 4.041, year: 2020
Method of publishing: Open access
https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-020-00577-6#citeas

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.
Permanent Link: http://hdl.handle.net/11104/0307384