| Autor: |
Robin N. Stringer, Bohumila Jurkovicova-Tarabova, Sun Huang, Omid Haji-Ghassemi, Romane Idoux, Anna Liashenko, Ivana A. Souza, Yuriy Rzhepetskyy, Lubica Lacinova, Filip Van Petegem, Gerald W. Zamponi, Roger Pamphlett, Norbert Weiss |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Molecular Brain, Vol 13, Iss 1, Pp 1-11 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
1756-6606 |
| DOI: |
10.1186/s13041-020-00577-6 |
| Popis: |
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 CACNA1H variants may be risk factors in the complex etiology of ALS. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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