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

David Brenner,Serena Lattante,Albert C. Ludolph,Peter M. Andersen,Antje Knehr,Jochen H. Weishaupt,Kathrin Müller,Rüstem Yilmaz,Axel Freischmidt

doi: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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease
We extend the previous knowledge about FUS/TBK1 double-mutant patients by whole-exome sequencing of additional 28 patients with FUS mutation
We report and summarize eight patients with rare variants in both FUS and TBK1, weigh the evidence for their pathogenicity, and study the phenotype of double-mutant compared to single-mutant ALS patients

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Its heritability is estimated to be in the range of 30–60%. Mutations in the RNA-binding protein FUS can cause ALS and FTD in very rare instances. The heterozygous ALS- and FTD-causing mutations in TBK1 usually lead to a loss of function of one TBK1 allele and have been suggested to impair the cellular role of TBK1 in autophagy and glial immune responses [5]. Both genes act most likely at an upstream position in different cellular pathways. We and others have previously described several ALS patients with simultaneous mutations in FUS and TBK1 [11, 12]. We compare the co-segregation of genotypes and phenotypes in two families in which mutations in TBK1 and FUS occur separately or in combination and compare them with previously reported and newly identified TBK1/FUS double-mutant patients

Methods

Results

Conclusion