Molecular Brain, 2020
Stringer, R. N., Jurkovicova-Tarabova, B., Huang, S., Haji-Ghassemi, O., Idoux, R., Liashenko, A., … Weiss, N. (2020). A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity. Molecular Brain.
Stringer, Robin N, Bohumila Jurkovicova-Tarabova, Sun Huang, O. Haji-Ghassemi, Romane Idoux, A. Liashenko, I. A. Souza, et al. “A Rare CACNA1H Variant Associated with Amyotrophic Lateral Sclerosis Causes Complete Loss of Cav3.2 T-Type Channel Activity.” Molecular Brain (2020).
Stringer, Robin N., et al. “A Rare CACNA1H Variant Associated with Amyotrophic Lateral Sclerosis Causes Complete Loss of Cav3.2 T-Type Channel Activity.” Molecular Brain, 2020.
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.