TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064190%3A_____%2F17%3AN0000135" target="_blank" >RIV/00064190:_____/17:N0000135 - isvavai.cz</a>
Výsledek na webu
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324646/pdf/HUMU-38-297.pdf" target="_blank" >https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324646/pdf/HUMU-38-297.pdf</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/humu.23161" target="_blank" >10.1002/humu.23161</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Popis výsledku v původním jazyce
We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
Název v anglickém jazyce
TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Popis výsledku anglicky
We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
Klasifikace
Druh
J<sub>SC</sub> - Článek v periodiku v databázi SCOPUS
CEP obor
—
OECD FORD obor
30103 - Neurosciences (including psychophysiology)
Návaznosti výsledku
Projekt
—
Návaznosti
V - Vyzkumna aktivita podporovana z jinych verejnych zdroju
Ostatní
Rok uplatnění
2017
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Human Mutation
ISSN
1059-7794
e-ISSN
1098-1004
Svazek periodika
38
Číslo periodika v rámci svazku
3
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
13
Strana od-do
297-309
Kód UT WoS článku
—
EID výsledku v databázi Scopus
2-s2.0-85010775170