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Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

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dc.contributor.authorFreischmidt, Axel
dc.contributor.authorWieland, Thomas
dc.contributor.authorRichter, Benjamin
dc.contributor.authorRuf, Wolfgang
dc.contributor.authorSchaeffer, Veronique
dc.contributor.authorMüller, Kathrin
dc.contributor.authorMarroquin, Nicolai
dc.contributor.authorNordin, Frida
dc.contributor.authorHübers, Annemarie
dc.contributor.authorWeydt, Patrick
dc.contributor.authorPinto, Susana
dc.contributor.authorPress, Rayomond
dc.contributor.authorMillecamps, Stéphanie
dc.contributor.authorMolko, Nicolas
dc.contributor.authorBernard, Emilien
dc.contributor.authorDesnuelle, Claude
dc.contributor.authorSoriani, Marie-Hélène
dc.contributor.authorDorst, Johannes
dc.contributor.authorGraf, Elisabeth
dc.contributor.authorNordström, Ulrika
dc.contributor.authorFeiler, Marisa S.
dc.contributor.authorPutz, Stefan
dc.contributor.authorBoeckers, Tobias M.
dc.contributor.authorMeyer, Thomas
dc.contributor.authorWinkler, Andrea S.
dc.contributor.authorWinkelman, Juliane
dc.contributor.authorCarvalho, Mamede
dc.contributor.authorThal, Dietmar R.
dc.contributor.authorOtto, Markus
dc.contributor.authorBrännström, Thomas
dc.contributor.authorVolk, Alexander E
dc.contributor.authorKursula, Petri
dc.contributor.authorDanzer, Karin M.
dc.contributor.authorLichtner, Peter
dc.contributor.authorDikic, Ivan
dc.contributor.authorMeitinger, Thomas
dc.contributor.authorLudolph, Albert C.
dc.contributor.authorStrom, Tim M.
dc.contributor.authorAndersen, Peter M.
dc.contributor.authorWeishaupt, Jochen H.
dc.date.accessioned2021-06-08T12:27:34Z
dc.date.available2021-06-08T12:27:34Z
dc.date.issued2015
dc.descriptionCopyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.pt_PT
dc.description.abstractAmyotrophic 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Neurosci. 2015 May;18(5):631-636pt_PT
dc.identifier.doi10.1038/nn.4000pt_PT
dc.identifier.eissn1546-1726
dc.identifier.issn1097-6256
dc.identifier.urihttp://hdl.handle.net/10451/48405
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relation.publisherversionhttps://www.nature.com/neuro/pt_PT
dc.titleHaploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage636pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage631pt_PT
oaire.citation.titleNature Neurosciencept_PT
oaire.citation.volume18pt_PT
person.familyNamePinto
person.familyNamede Carvalho
person.givenNameSusana
person.givenNameMamede
person.identifier593760
person.identifier.ciencia-idD31B-E89C-CB94
person.identifier.orcid0000-0002-0727-5897
person.identifier.orcid0000-0001-7556-0158
person.identifier.ridL-8394-2019
person.identifier.scopus-author-id23397978500
person.identifier.scopus-author-id7101893769
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication3fa09e71-c9b7-4536-a359-f7e3576dca09
relation.isAuthorOfPublicationdd7f55d4-c2b5-4fd2-9bd1-a9542a62f58f
relation.isAuthorOfPublication.latestForDiscoverydd7f55d4-c2b5-4fd2-9bd1-a9542a62f58f

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