| Literature DB >> 25803835 |
Axel Freischmidt1, Thomas Wieland2, Benjamin Richter3, Wolfgang Ruf1, Veronique Schaeffer3, Kathrin Müller1, Nicolai Marroquin4, Frida Nordin5, Annemarie Hübers1, Patrick Weydt1, Susana Pinto6, Rayomond Press7, Stéphanie Millecamps8, Nicolas Molko9, Emilien Bernard10, Claude Desnuelle11, Marie-Hélène Soriani11, Johannes Dorst1, Elisabeth Graf2, Ulrika Nordström5, Marisa S Feiler1, Stefan Putz12, Tobias M Boeckers12, Thomas Meyer13, Andrea S Winkler14, Juliane Winkelman14, Mamede de Carvalho15, Dietmar R Thal16, Markus Otto1, Thomas Brännström17, Alexander E Volk18, Petri Kursula19, Karin M Danzer1, Peter Lichtner2, Ivan Dikic3, Thomas Meitinger20, Albert C Ludolph1, Tim M Strom21, Peter M Andersen22, Jochen H Weishaupt1.
Abstract
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.Entities:
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Year: 2015 PMID： 25803835 DOI： 10.1038/nn.4000
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884