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Loss-of-function BK channel mutation causes impaired mitochondria and progressive cerebellar ataxia.

Abstract：

:Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the gene KCNMA1, encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BKG354S) in KCNMA1, in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BKG354S channel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BKG354S cells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BKG354S channel, but not the BKWT channel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Du X,Carvalho-de-Souza JL,Wei C,Carrasquel-Ursulaez W,Lorenzo Y,Gonzalez N,Kubota T,Staisch J,Hain T,Petrossian N,Xu M,Latorre R,Bezanilla F,Gomez CM

doi

10.1073/pnas.1920008117

subject

Has Abstract

pub_date

2020-03-17 00:00:00

pages

6023-6034

issue

11

eissn

0027-8424

issn

1091-6490

pii

1920008117

journal_volume

117

pub_type

杂志文章

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