2017
DOI: 10.1002/humu.23161
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TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

Abstract: 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 wa… Show more

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Cited by 91 publications
(73 citation statements)
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“…This patient carried the p.N254Kfs*4 TBK1 mutation and a missense variant (p.P392L) in the sequestosome 1 ( SQSTM1 ) gene. Among TBK1 mutation carriers, three of them (cases carrying the p.K30_E76del, p.G272_T331del or p.T79del) have been recently reported in an independent study aimed at investigating the genetic contribution of TBK1 in an extended European cohort of patients belonging to the ALS/FTD disease continuum 18. These three patients were included in our exome sequencing project during the European cohort sample recruitment, and TBK1 mutation status was unknown at the time of exome sequencing.…”
Section: Resultsmentioning
confidence: 99%
“…This patient carried the p.N254Kfs*4 TBK1 mutation and a missense variant (p.P392L) in the sequestosome 1 ( SQSTM1 ) gene. Among TBK1 mutation carriers, three of them (cases carrying the p.K30_E76del, p.G272_T331del or p.T79del) have been recently reported in an independent study aimed at investigating the genetic contribution of TBK1 in an extended European cohort of patients belonging to the ALS/FTD disease continuum 18. These three patients were included in our exome sequencing project during the European cohort sample recruitment, and TBK1 mutation status was unknown at the time of exome sequencing.…”
Section: Resultsmentioning
confidence: 99%
“…From a biological perspective, the pathogenicity of the Arg573Gly change was in doubt according to (1) SIFT program prediction as tolerated3; (2) in vitro protein activity studied through the NFκB/interferon pathway showing no reduction3; and (3) because of its location outside the kinase domain, the main functional region of the protein housing its catalytic activity 5. However, the presence of clear cosegregation supports pathogenicity and opens the possibility of other mutations located outside the kinase domain being pathogenic.…”
Section: Discussionmentioning
confidence: 99%
“…However, pathogenicity of many TBK1 missense mutations is difficult to establish in the absence of cosegregation data. A screening for TBK1 mutations carried out by the European Early-Onset Dementia (EU EOD) Consortium in a large series of FTD/ALS cases found one carrier of the Arg573Gly mutation 3. The index case belonged to a Spanish family with autosomal dominant disease manifesting in the sixth decade as either dementia or PLS, and in whom we were able to demonstrate cosegregation.…”
mentioning
confidence: 82%
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“…3d) and extramotor sites, also corresponding to Brettschneider stage 4. An extensive neuropathological report on patient 10 was previously published [18]. …”
Section: Resultsmentioning
confidence: 99%