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A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity
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SYSNO ASEP 0522971 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity Tvůrce(i) Stringer, Robin Nicholas (UOCHB-X)
Jurkovicova-Tarabova, B. (SK)
Huang, S. (CA)
Haji-Ghassemi, O. (CA)
Idoux, R. (CZ)
Liashenko, A. (CZ)
Souza, I. A. (CA)
Rzhepetskyy, Yuriy (UOCHB-X)
Lacinová, L. (SK)
Van Petegem, F. (CA)
Zamponi, G. W. (CA)
Pamphlett, R. (AU)
Weiss, Norbert (UOCHB-X) ORCID, RIDČíslo článku 33 Zdroj.dok. Molecular Brain. - : BioMed Central
Roč. 13, Mar 6 (2020)Poč.str. 11 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova ALS ; amyotrophic lateral sclerosis ; motor neuron disease ; CACNA1H ; mutation ; calcium channel ; Cav3.2 channel ; T-type channel ; biophysics Vědní obor RIV CE - Biochemie Obor OECD Biochemistry and molecular biology Způsob publikování Open access Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000519056200001 EID SCOPUS 85081258312 DOI 10.1186/s13041-020-00577-6 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2021 Elektronická adresa https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-020-00577-6#citeas
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