Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F19%3A10396785" target="_blank" >RIV/00216208:11310/19:10396785 - isvavai.cz</a>

Alternative codes found

RIV/68378050:_____/19:00521722

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=9crJq-ZOdM" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=9crJq-ZOdM</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1212/NXG.0000000000000359" target="_blank" >10.1212/NXG.0000000000000359</a>

Result language

angličtina

Original language name

Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia

Original language description

Objective To investigate the pathogenicity of a novel homozygous BRAT1 variant in 2 siblings with nonprogressive cerebellar ataxia (NPCA) through functional studies on primary and immortalized patient cell lines. Methods BRAT1 protein levels and ataxia-telangiectasia mutated (ATM) kinase activity in patient-derived and control cell lines were assessed by Western blotting. The impact of the novel BRAT1 variants on mitochondrial function was also assessed, by comparing patient and control cell lines for rates of oxygen consumption and for phosphorylation (S293) of the E1APL FUNCTIONAL SYMBOL ALPHA subunit of pyruvate dehydrogenase (PDH). Results Two male siblings with NPCA, mild intellectual disability, and isolated cerebellar atrophy were found to be homozygous for a c.185T&gt;A (p.Val62Glu) variant in BRAT1 by whole exome sequencing. Western blotting revealed markedly decreased BRAT1 protein levels in lymphocytes and/or fibroblast cells from both affected siblings compared to control cell lines. There were no differences between the patient and control cells in ATM kinase activation, following ionizing radiation. Mitochondrial studies were initially suggestive of a defect in regulation of PDH activity, but there was no evidence of increased phosphorylation of the E1APL FUNCTIONAL SYMBOL ALPHA subunit of the PDH complex. Measurement of oxygen consumption rates similarly failed to identify differences between patient and control cells. Conclusions Biallelic pathogenic variants in BRAT1 can be associated with NPCA, a phenotype considerably milder than previously reported. Surprisingly, despite the molecular role currently proposed for BRAT1 in ATM regulation, this disorder is unlikely to result from defective ATM kinase or mitochondrial dysfunction.

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

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

—

Continuities

S - Specificky vyzkum na vysokych skolach

Publication year

2019

Confidentiality

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

Name of the periodical

Neurology. Genetics [online]

ISSN

2376-7839

e-ISSN

2376-7839

Volume of the periodical

5

Issue of the periodical within the volume

5

Country of publishing house

US - UNITED STATES

Number of pages

7

Pages from-to

e359

UT code for WoS article

000512892500007

EID of the result in the Scopus database

2-s2.0-85079417420