Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/68378050:_____/19:00521722

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Homozygous pathogenic variant in BRAT1 associated with nonprogressive cerebellar ataxia

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2019

Kód důvěrnosti údajů

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

Název periodika

Neurology. Genetics [online]

ISSN

2376-7839

e-ISSN

2376-7839

Svazek periodika

5

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

7

Strana od-do

e359

Kód UT WoS článku

000512892500007

EID výsledku v databázi Scopus

2-s2.0-85079417420