Mutational analysis of TBK1 in Taiwanese patients with amyotrophic lateral sclerosis

Abstract Mutations in the TBK1 gene were just recently identified to cause amyotrophic lateral sclerosis (ALS), and their role in ALS in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in TBK1 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of TBK1 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 168 patients remained elusive after mutations in SOD1 , C9ORF72 , TARDBP , FUS , ATXN2 , OPTN , VCP , UBQLN2 , SQSTM1 , PFN1 , HNRNPA1 , HNRNPA2B1 , MATR3 , CHCHD10 , and TUBA4A had been excluded. We identified one nonsense mutation, p.R444X (c.1330C>T), in one patient with apparently sporadic ALS-frontotemporal dementia. In vitro functional study demonstrated the p.R444X mutation resulting in a truncated TANK-binding kinase 1 (TBK1) protein product, low protein expression, and loss of kinase function and interaction with optineurin. The frequency of TBK1 mutations in ALS patients in Taiwan is, therefore, approximately 0.5% (1/207). This study reports a novel TBK1 mutation and stresses on the importance to consider TBK1 mutation as a possible etiology of ALS.