Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
| العنوان: | Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia |
|---|---|
| المؤلفون: | Susana Pinto, Axel Freischmidt, Thomas Wieland, Markus Otto, Emilien Bernard, Dietmar Rudolf Thal, Peter M Andersen, Stéphanie Millecamps, Nicolai Marroquin, Marie-Hélène Soriani, Albert C. Ludolph, Andrea Sylvia Winkler, Alexander E Volk, Marisa S. Feiler, Annemarie Hübers, Veronique Schaeffer, Johannes Dorst, Benjamin Richter, Kathrin Muller, Wolfgang Ruf, Claude Desnuelle, Petri Kursula, Tobias M. Boeckers, Jochen H. Weishaupt, Ulrika Nordström, Ivan Dikic, Frida Nordin, Elisabeth Graf, Karin M Danzer, Rayomond Press, Thomas F. Meyer, Patrick Weydt, Mamede de Carvalho, Thomas Meitinger, Thomas Brännström, Stefan Putz, Juliane Winkelman, Nicolas Molko, Peter Lichtner, Tim M. Strom |
| المساهمون: | Repositório da Universidade de Lisboa |
| المصدر: | Nature Neuroscience Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| بيانات النشر: | Springer Nature, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, DNA Mutational Analysis, Mutation, Missense, Cell Cycle Proteins, Genome-wide association study, Protein Serine-Threonine Kinases, Biology, Genetic Heterogeneity, Gene Frequency, Transcription Factor TFIIIA, medicine, Humans, Missense mutation, Exome, Amyotrophic lateral sclerosis, Alleles, Cells, Cultured, Exome sequencing, Optineurin, Genetics, Genetic heterogeneity, General Neuroscience, Amyotrophic Lateral Sclerosis, Membrane Transport Proteins, Sequence Analysis, DNA, medicine.disease, Pedigree, Protein Structure, Tertiary, Europe, Codon, Nonsense, Frontotemporal Dementia, Female, Haploinsufficiency, Neuroscience, Genome-Wide Association Study |
| الوصف: | Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia. |
| وصف الملف: | application/pdf; Print-Electronic |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1bdb841093118945deed0ba38a5f0afTest https://hdl.handle.net/10451/48405Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d1bdb841093118945deed0ba38a5f0af |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |