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FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees

Mutations in FUS and TBK1 often cause aggressive early-onset amyotrophic lateral sclerosis (ALS) or a late-onset ALS and/or frontotemporal dementia (FTD) phenotype, respectively. Co-occurrence of mutations in two or more Mendelian ALS/FTD genes has been repeatedly reported. However, little is known...

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Main Authors: Brenner, David (Author) , Müller, Kathrin (Author) , Lattante, Serena (Author) , Yılmaz, Rüstem (Author) , Knehr, Antje (Author) , Freischmidt, Axel (Author) , Ludolph, Albert C. (Author) , Andersen, Peter M. (Author) , Weishaupt, Jochen H. (Author)
Format: Article (Journal)
Language:English
Published: 2022
In: Neurogenetics
Year: 2022, Volume: 23, Pages: 59-65
ISSN:1364-6753
DOI:10.1007/s10048-021-00671-4
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s10048-021-00671-4
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Author Notes:David Brenner, Kathrin Müller, Serena Lattante, Rüstem Yilmaz, Antje Knehr, Axel Freischmidt, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt
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Summary:Mutations in FUS and TBK1 often cause aggressive early-onset amyotrophic lateral sclerosis (ALS) or a late-onset ALS and/or frontotemporal dementia (FTD) phenotype, respectively. Co-occurrence of mutations in two or more Mendelian ALS/FTD genes has been repeatedly reported. However, little is known how two pathogenic ALS/FTD mutations in the same patient interact to shape the final phenotype. We screened 28 ALS patients with a known FUS mutation by whole-exome sequencing and targeted evaluation for mutations in other known ALS genes followed by genotype-phenotype correlation analysis of FUS/TBK1 double-mutant patients. We report on new and summarize previously published FUS and TBK1 double-mutant ALS/FTD patients and their families. We found that, within a family, mutations in FUS cause ALS while TBK1 single mutations are observed in FTD patients. FUS/TBK1 double mutations manifested as ALS and without a manifest difference regarding age at onset and disease duration when compared to FUS single-mutant individuals. In conclusion, TBK1 and FUS variants do not seem to interact in a simple additive way. Rather, the phenotype of FUS/TBK1 double-mutant patients appears to be dominated by the FUS mutation.
Item Description:Published online: 13 September 2021
Gesehen am 16.01.2023
Physical Description:Online Resource
ISSN:1364-6753
DOI:10.1007/s10048-021-00671-4

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