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.

Brenner, D., Muller, K., Lattante, S., Yilmaz, R., Knehr, A., Freischmidt, A., Ludolph, A. C., Andersen, P. M., Weishaupt, J. H., FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees, <<NEUROGENETICS>>, 2022; 23 (1): 59-65. [doi:10.1007/s10048-021-00671-4] [http://hdl.handle.net/10807/196423]

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

Lattante, S.;
2022

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.
Inglese
Brenner, D., Muller, K., Lattante, S., Yilmaz, R., Knehr, A., Freischmidt, A., Ludolph, A. C., Andersen, P. M., Weishaupt, J. H., FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees, <<NEUROGENETICS>>, 2022; 23 (1): 59-65. [doi:10.1007/s10048-021-00671-4] [http://hdl.handle.net/10807/196423]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/196423
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