Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia

Ann Neurol. 2013 Apr;73(4):546-53. doi: 10.1002/ana.23832. Epub 2013 Feb 19.

Abstract

Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.12-13. Exome sequencing in 2 cousins identified a single cosegregating mutation (p.R2G) in the β-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the β-tubulin autoregulatory MREI (methionine-arginine-glutamic acid-isoleucine) domain, highly expressed in the central nervous system, and extensive in vitro work has previously demonstrated that substitutions at residue 2, specifically R2G, disrupt the autoregulatory capability of the wild-type β-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Australia
  • Brain / pathology
  • Dystonic Disorders / genetics*
  • Dystonic Disorders / pathology
  • England
  • Exome
  • Female
  • Genetic Linkage
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics
  • Tubulin / genetics*

Substances

  • TUBB4A protein, human
  • Tubulin