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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F20%3A00522971" target="_blank" >RIV/61388963:_____/20:00522971 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11120/20:43919915

Result on the web

<a href="https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-020-00577-6#citeas" target="_blank" >https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-020-00577-6#citeas</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s13041-020-00577-6" target="_blank" >10.1186/s13041-020-00577-6</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Molecular Brain

ISSN

1756-6606

e-ISSN

—

Volume of the periodical

13

Issue of the periodical within the volume

Mar 6

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

33

UT code for WoS article

000519056200001

EID of the result in the Scopus database

2-s2.0-85081258312