TBK1 is associated with ALS and ALS-FTD in Sardinian patients

Giuseppe Borghero, Maura Pugliatti, Francesco Marrosu, Maria Giovanna Marrosu, Maria Rita Murru, Gianluca Floris, Antonino Cannas, Patrizia Occhineri, Tea B. Cau, Daniela Loi, Anna Ticca, Sebastiano Traccis, Umberto Manera, Antonio Canosa, Cristina Moglia, Andrea Calvo, Marco Barberis, Maura Brunetti, Raphael J. Gibbs, Alan E. RentonEdoardo Errichiello, Magdalena Zoledziewska, Antonella Mulas, Yong Qian, Jun Din, Hannah A. Pliner, Bryan J. Traynor, Adriano Chiò, ITALSGEN and SARDINALS Consortia, Gabriele Mora, Kalliopi Marinou Aktipi

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Recently, mutations in the TANK-binding kinase 1 (TBK1) gene were identified as a cause for amyotrophic lateral sclerosis (ALS) with or without comorbid frontotemporal dementia. We have assessed the frequency and clinical characteristics of TBK1 mutations in a cohort of ALS patients of Sardinian ancestry. Whole-exome sequencing was performed on Hiseq2000 platform (Illumina). Genome analysis Toolkit was used to align and to code variants according to Human Genome (UCSC hg19). Mutation was confirmed with Sanger sequence. In our screening of 186 Sardinian ALS cases, we found 3 (1.6%) patients carrying 3 distinct novel genetic variants: a nonsynonymous SNV c.1150C>T leading to a p.Arg384Thr change in exon 9; a nonsynonymous SNV c.1331G>A causes a p.Arg444Gln change in exon 11; and a frameshift deletion c.2070delG (p.Met690fs) at the exon 20 of the gene leading to a stop at 693 codon. The latter patients also carried missense mutation c.98C>T of the SQSTM1 gene causing a substitution of an arginine with a valine at the position 33 (p.Arg33Val). All variants were found to be deleterious according to in silico predictions. All cases were apparently sporadic and one of them showed frontotemporal dementia associated to ALS. These mutations were not found in 2 cohorts of 6780 ethnic-matched controls. We have found that TBK1 mutations account for 1.6% of Sardinian ALS cases. Our data support the notion that TBK1 is a novel ALS gene, providing important evidence complementary to the first descriptions.

Original languageEnglish
Pages (from-to)180.e1-5
JournalNeurobiology of Aging
Publication statusPublished - Jul 2016


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