FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees
Open Access
- 13 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in neurogenetics
- Vol. 23 (1), 59-65
- https://doi.org/10.1007/s10048-021-00671-4
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.Funding Information
- Ruprecht-Karls-Universität Heidelberg
This publication has 16 references indexed in Scilit:
- ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase functionNeurobiology of Aging, 2018
- Comprehensive analysis of the mutation spectrum in 301 German ALS familiesJournal of Neurology, Neurosurgery & Psychiatry, 2018
- ALS Genes in the Genomic Era and their Implications for FTDTrends in Genetics, 2018
- TBK1mutations in Italian patients with amyotrophic lateral sclerosis: genetic and functional characterisationJournal of Neurology, Neurosurgery & Psychiatry, 2017
- Amyotrophic lateral sclerosis: recent genetic highlightsCurrent Opinion in Neurology, 2016
- Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementiaNature Neuroscience, 2015
- Evidence for an oligogenic basis of amyotrophic lateral sclerosisHuman Molecular Genetics, 2012
- EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) – revised report of an EFNS task forceEuropean Journal of Neurology, 2011
- Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral SclerosisScience, 2009
- Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6Science, 2009