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

Molecular Brain
Robin N StringerNorbert Weiss

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 CACNA1...Continue Reading

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Citations

Jul 9, 2020·Pflügers Archiv : European journal of physiology·Philippe LoryArnaud Monteil
Jul 6, 2021·Journal of Agricultural and Food Chemistry·Yaping ZhouQinlu Lin

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Methods Mentioned

BETA
co-immunoprecipitations
co-immunoprecipitation
transfection
immunoprecipitation

Software Mentioned

Clampfit
pClamp
Fitmaster
Patchmaster
ImageJ
Origin Pro

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