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

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dc.contributor.authorStringer, Robin N
dc.contributor.authorJurkovicova-Tarabova, Bohumila
dc.contributor.authorHuang, Sun
dc.contributor.authorHaji-Ghassemi, Omid
dc.contributor.authorIdoux, Romane
dc.contributor.authorLiashenko, Anna
dc.contributor.authorSouza, Ivana A
dc.contributor.authorRzhepetskyy, Yuriy
dc.contributor.authorLacinova, Lubica
dc.contributor.authorVan Petegem, Filip
dc.contributor.authorZamponi, Gerald W
dc.contributor.authorPamphlett, Roger
dc.contributor.authorWeiss, Norbert
dc.date.accessioned2020-03-08T01:02:34Z
dc.date.available2020-03-08T01:02:34Z
dc.date.issued2020-03-06
dc.date.updated2020-03-08T01:02:33Z
dc.description.abstractAbstract 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.
dc.identifier.citationMolecular Brain. 2020 Mar 06;13(1):33
dc.identifier.doihttps://doi.org/10.1186/s13041-020-00577-6
dc.identifier.urihttp://hdl.handle.net/1880/111722
dc.identifier.urihttps://doi.org/10.11575/PRISM/44360
dc.language.rfc3066en
dc.rights.holderThe Author(s)
dc.titleA rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity
dc.typeJournal Article
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