A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Ca(v)3.2 T-type channel activity
Abstrakt
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 Ca(v)3.2 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 Ca(v)3.2 (p.Delta I153) 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 Ca(v)3.2 channel activity.
The newly identified Delta I153 variant is the first to be reported to cause a complete loss of Ca(v)3.2 channel function. These findings add to the notion that loss-of-function of Ca(v)3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.