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

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• 作者：Giuseppe Borghero^a ; Maura Pugliatti^b ; Francesco Marrosu^a ; Maria Giovanna Marrosu^c ; Maria Rita Murru^c ; Gianluca Floris^a ; Antonino Cannas^a ; Patrizia Occhineri^b ; Tea B. Cau^d ; Daniela Loi^d ; Anna Ticca^e ; Sebastiano Traccis^f ; Umberto Manera^g ; Antonio Canosa^g ; ^h ; Cristina Moglia^g ; Andrea Calvo^g ; ⁱ ; Marco Barberis^g ; Maura Brunetti^g ; J. Raphael Gibbsⁱ ; Alan E. Renton^j ; Edoardo Errichiello^j ; ^g ; Magdalena Zoledziewska^k ; ^l ; ^m ; Antonella Mulas^m ; Yong Qianⁿ ; Jun Dinⁿ ; Hannah A. Pliner^j ; Bryan J. Traynor^j ; ^o ; Adriano Chiò ; ^g ; ⁱ ; ^p ; ^q ; ^{achio@usa.net" class="auth_mail" title="E-mail the corresponding author} ; for the ITALSGEN ; SARDINALS ConsortiaFrancesco O. Logullo ; Isabella Simone ; Giancarlo Logroscino ; Fabrizio Salvi ; Ilaria Bartolomei ; Margherita Capasso ; Claudia Caponnetto ; Paolo Mandich ; Gianluigi Mancardi ; Paola Origone ; Francesca L. Conforti ; Giuseppe Vita ; Sonia Messina ; Massimo Russo ; Gabriele Mora ; Kalliopi Marinou ; Riccardo Sideri ; Christian Lunetta ; Silvana Penco ; Lorena Mosca ; Giuseppe Lauria Pinter ; Massimo Corbo ; Nilo Riva ; Paola Carrera ; Paolo Volanti ; Lucio Tremolizzo ; Carlo Ferrarese ; Nicola Fini ; Antonio Fasano ; Maria Rosaria Monsurrò ; Gioacchino Tedeschi ; Francesca Trojsi ; Giovanni Piccirillo ; Viviana Cristillo ; Letizia Mazzini ; Sandra D'Alfonso ; Anna Bersano ; Lucia Corrado ; Alessandra Bagarotti ; Vincenzo La Bella ; Rossella Spataro ; Tiziana Colletti ; Mario Sabatelli ; Marcella Zollino ; Amelia Conte ; Marco Luigetti ; Serena Lattante ; Giuseppe Marangi ; Marialuisa Santarelli ; Antonio Petrucci ; Fabio Giannini ; Stefania Battistini ; Claudia Ricci ; Michele Benigni ; Gabriella Restagno ; Federico Casale ; Giuseppe Marrali ; Giuseppe Fuda ; Irene Ossola ; Stefania Cammarosano ; Antonio Ilardi ; Davide Bertuzzo ; Raffaella Tanel ; Fabrizio Pisano ; Emanuela Costantino ; Carla Pani ; Roberta Puddu ; Carla Caredda ; Valeria Piras ; Stefania Tranquilli ; Stefania Cuccu ; Daniela Corongiu ; Maurizio Melis ; Antonio Milia ; Angelo Pirisi ; Leslie D. Parish ; Enzo Ortu
• 关键词：Amyotrophic lateral sclerosis ; Genetics ; Sporadic ; TBK1
• 刊名：Neurobiology of Aging
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：43
• 期：Complete
• 页码：180.e1-180.e5
• 全文大小：836 K

文摘

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.