title: TBK1 is associated with ALS and ALS-FTD in Sardinian patients.
abstract: 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.
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borghero
authors.affiliation: Department of Biomedical and Surgical Sciences, Section of Neurological, Psychiatric and Psychological Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Pugliatti
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marrosu
authors.affiliation: Department of Medical Sciences, Multiple Sclerosis Center, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.affiliation: Department of Medical Sciences, Multiple Sclerosis Center, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Murru
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Floris
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cannas
authors.affiliation: Department of Biomedical and Surgical Sciences, Section of Neurological, Psychiatric and Psychological Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Occhineri
authors.affiliation: Azienda Sanitaria Locale n. 2, Olbia-Tempio, Olbia, Italy.
authors.forename: Tea B
authors.initials: TB
authors.lastname: Cau
authors.affiliation: Azienda Sanitaria Locale n. 2, Olbia-Tempio, Olbia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Loi
authors.affiliation: Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ticca
authors.affiliation: Department of Neurology, Ospedale Antonio Segni, Ozieri, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Traccis
authors.affiliation: "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Manera
authors.affiliation: "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Canosa
authors.affiliation: "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Moglia
authors.affiliation: "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.affiliation: "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Barberis
authors.affiliation: "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Brunetti
authors.affiliation: Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Renton
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA; "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Errichiello
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA; Computational Biology Core, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA; Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Laboratory of Genetics, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Laboratory of Genetics, National Institute on Aging, NIH, Baltimore, MD, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Din
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Pliner
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA; Department of Neurology, Brain Science Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.affiliation: "Rita Levi Montalcini" Department of Neuroscience, Amyotrophic Lateral Sclerosis Center, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Neuroscience Institute of Torino (NIT), Turin, Italy; Institute of Cognitive Sciences and Technologies, Consiglio Nazionale delle Ricerche, Rome, Italy. Electronic address: achio@usa.net.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007558:Italy; D008297:Male; D009154:Mutation; D017346:Protein Serine-Threonine Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human
keywords: Amyotrophic lateral sclerosis; Genetics; Sporadic; TBK1