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

Hersheson, J; Mencacci, NE; Davis, M; MacDonald, N; Trabzuni, D; Ryten, M; Pittman, A; Paudel, R; Kara, E; Fawcett, K; et al. Hersheson, J; Mencacci, NE; Davis, M; MacDonald, N; Trabzuni, D; Ryten, M; Pittman, A; Paudel, R; Kara, E; Fawcett, K; Plagnol, V; Bhatia, KP; Medlar, AJ; Stanescu, HC; Hardy, J; Kleta, R; Wood, NW; Houlden, H (2013) Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia. Ann Neurol, 73 (4). pp. 546-553. ISSN 1531-8249 https://doi.org/10.1002/ana.23832
SGUL Authors: Pittman, Alan Michael

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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.

Item Type: Article
Keywords: Adult, Animals, Australia, Brain, Dystonic Disorders, England, Exome, Female, Genetic Linkage, Genetic Predisposition to Disease, Genotype, Humans, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Tubulin, Brain, Animals, Humans, Dystonic Disorders, Genetic Predisposition to Disease, Tubulin, Pedigree, Genotype, Mutation, Polymorphism, Single Nucleotide, Adult, Middle Aged, Australia, England, Female, Male, Genetic Linkage, Exome, 1103 Clinical Sciences, 1109 Neurosciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Ann Neurol
ISSN: 1531-8249
Language: eng
Dates:
DateEvent
21 May 2013Published
19 February 2013Published Online
5 November 2012Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
G0802462Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G-0907Parkinson's UKhttp://dx.doi.org/10.13039/501100000304
MC_G0901330Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1001253Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G108/638Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_G1000735Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
089698Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MR/J004758/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0802760Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G-1107Parkinson's UKhttp://dx.doi.org/10.13039/501100000304
MC_PC_09003Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 23424103
Web of Science ID: WOS:000319523800016
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/111064
Publisher's version: https://doi.org/10.1002/ana.23832

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