1. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.
- Author
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Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, Marroquin N, Nordin F, Hübers A, Weydt P, Pinto S, Press R, Millecamps S, Molko N, Bernard E, Desnuelle C, Soriani MH, Dorst J, Graf E, Nordström U, Feiler MS, Putz S, Boeckers TM, Meyer T, Winkler AS, Winkelman J, de Carvalho M, Thal DR, Otto M, Brännström T, Volk AE, Kursula P, Danzer KM, Lichtner P, Dikic I, Meitinger T, Ludolph AC, Strom TM, Andersen PM, and Weishaupt JH
- Subjects
- Alleles, Amyotrophic Lateral Sclerosis epidemiology, Cell Cycle Proteins, Cells, Cultured, Codon, Nonsense, DNA Mutational Analysis, Europe epidemiology, Female, Frontotemporal Dementia epidemiology, Gene Frequency, Genetic Heterogeneity, Genome-Wide Association Study, Humans, Male, Membrane Transport Proteins, Mutation, Missense, Pedigree, Protein Serine-Threonine Kinases biosynthesis, Protein Serine-Threonine Kinases genetics, Protein Structure, Tertiary, Sequence Analysis, DNA, Transcription Factor TFIIIA metabolism, Amyotrophic Lateral Sclerosis genetics, Exome, Frontotemporal Dementia genetics, Protein Serine-Threonine Kinases deficiency
- 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.
- Published
- 2015
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