Change search
ReferencesLink to record
Permanent link

Direct link
Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
Show others and affiliations
2015 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 18, no 5, 631-+ p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 18, no 5, 631-+ p.
National Category
URN: urn:nbn:se:umu:diva-103728DOI: 10.1038/nn.4000ISI: 000353636900009PubMedID: 25803835OAI: diva2:818882
Available from: 2015-06-09 Created: 2015-05-28 Last updated: 2015-06-09Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Nordin, FridaNordström, UlrikaBrännström, ThomasAndersen, Peter M.
By organisation
Clinical NeuroscienceDepartment of Medical Biosciences
In the same journal
Nature Neuroscience

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 249 hits
ReferencesLink to record
Permanent link

Direct link