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

Molecular Brain

Lubica Lacinova¹  Bohumila Jurkovicova-Tarabova¹  Omid Haji-Ghassemi²  Filip Van Petegem²  Ivana A. Souza³  Gerald W. Zamponi³  Sun Huang³  Roger Pamphlett⁴  Robin N. Stringer⁵  Norbert Weiss⁵  Yuriy Rzhepetskyy⁵  Anna Liashenko⁵  Romane Idoux⁵ 

[1] Center of Biosciences, Institute of Molecular Physiology and Genetics, Academy of Sciences;Department of Biochemistry and Molecular Biology, University of British Columbia;Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary;Discipline of Pathology, Brain and Mind Centre, The University of Sydney;Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences;

关键词: ALS;    Amyotrophic lateral sclerosis;    Motor neuron disease;    CACNA1H;    Mutation;    Calcium channel;   

DOI  :  10.1186/s13041-020-00577-6

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown