2. Academic Validation
  3. Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia

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.
Joshua Hersheson 1,  Niccolo E Mencacci,  Mary Davis,  Nicola MacDonald,  Daniah Trabzuni,  Mina Ryten,  Alan Pittman,  Reema Paudel,  Eleanna Kara,  Katherine Fawcett,  Vincent Plagnol,  Kailash P Bhatia,  Alan J Medlar,  Horia C Stanescu,  John Hardy,  Robert Kleta,  Nicholas W Wood,  Henry Houlden
Affiliations

Affiliation

  • 1 Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom.
PMID: 23424103 DOI: 10.1002/ana.23832
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.

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