title: Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.
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.
authors: Department of Molecular Neuroscience, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom.
authors: Joshua
authors: J
authors: Hersheson
authors: Niccolo E
authors: NE
authors: Mencacci
authors: Mary
authors: M
authors: Davis
authors: Nicola
authors: N
authors: MacDonald
authors: Daniah
authors: D
authors: Trabzuni
authors: Mina
authors: M
authors: Ryten
authors: Alan
authors: A
authors: Pittman
authors: Reema
authors: R
authors: Paudel
authors: Eleanna
authors: E
authors: Kara
authors: Katherine
authors: K
authors: Fawcett
authors: Vincent
authors: V
authors: Plagnol
authors: Kailash P
authors: KP
authors: Bhatia
authors: Alan J
authors: AJ
authors: Medlar
authors: Horia C
authors: HC
authors: Stanescu
authors: John
authors: J
authors: Hardy
authors: Robert
authors: R
authors: Kleta
authors: Nicholas W
authors: NW
authors: Wood
authors: Henry
authors: H
authors: Houlden
mesh_terms: D000328:Adult; D000818:Animals; D001315:Australia; D001921:Brain / Q000473:pathology; D020821:Dystonic Disorders / Q000235:genetics* / Q000473:pathology; D004739:England; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014404:Tubulin / Q000235:genetics*
chemical_list: C582076:TUBB4A protein, human; D014404:Tubulin