Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

Nat Neurosci. 2015 May;18(5):631-6. doi: 10.1038/nn.4000. Epub 2015 Mar 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amyotrophic Lateral Sclerosis / epidemiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Cells, Cultured
  • Codon, Nonsense
  • DNA Mutational Analysis
  • Europe / epidemiology
  • Exome*
  • Female
  • Frontotemporal Dementia / epidemiology
  • Frontotemporal Dementia / genetics*
  • Gene Frequency
  • Genetic Heterogeneity
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mutation, Missense
  • Pedigree
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / deficiency*
  • Protein-Serine-Threonine Kinases / genetics
  • Sequence Analysis, DNA
  • Transcription Factor TFIIIA / metabolism

Substances

  • Codon, Nonsense
  • OPTN protein, human
  • Transcription Factor TFIIIA
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human