Stringer, Robin NJurkovicova-Tarabova, BohumilaHuang, SunHaji-Ghassemi, OmidIdoux, RomaneLiashenko, AnnaSouza, Ivana ARzhepetskyy, YuriyLacinova, LubicaVan Petegem, FilipZamponi, Gerald WPamphlett, RogerWeiss, Norbert2020-03-082020-03-082020-03-06Molecular Brain. 2020 Mar 06;13(1):33http://hdl.handle.net/1880/111722https://doi.org/10.11575/PRISM/44360Abstract 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.Journal Article2020-03-08enThe Author(s)https://doi.org/10.1186/s13041-020-00577-6