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

• Verfasst von: Brenner, David [VerfasserIn]
• Verfasst von: Müller, Kathrin [VerfasserIn]
• Verfasst von: Lattante, Serena [VerfasserIn]
• Verfasst von: Yılmaz, Rüstem [VerfasserIn]
• Verfasst von: Knehr, Antje [VerfasserIn]
• Verfasst von: Freischmidt, Axel [VerfasserIn]
• Verfasst von: Ludolph, Albert C. [VerfasserIn]
• Verfasst von: Andersen, Peter M. [VerfasserIn]
• Verfasst von: Weishaupt, Jochen H. [VerfasserIn]
• Titel: FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees
• Verf.angabe: David Brenner, Kathrin Müller, Serena Lattante, Rüstem Yilmaz, Antje Knehr, Axel Freischmidt, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt
• Jahr: 2022
• Umfang: 7 S.
• Fussnoten: Published online: 13 September 2021 ; Gesehen am 16.01.2023
• Titel Quelle: Enthalten in: Neurogenetics
• Ort Quelle: Berlin : Springer, 1997
• Jahr Quelle: 2022
• Band/Heft Quelle: 23(2022), Seite 59-65
• ISSN Quelle: 1364-6753
• DOI: doi:10.1007/s10048-021-00671-4
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ALS
• Sach-SW: Amyotrophic lateral sclerosis
• Sach-SW: Frontotemporal dementia
• Sach-SW: FTD
• Sach-SW: FUS
• Sach-SW: TBK1
• K10plus-PPN: 1831174731
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

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.