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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; (2013) Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia. Ann Neurol , 73 (4) 546 - 553. 10.1002/ana.23832.

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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.

Type: Article
Title: Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.
Location: United States
DOI: 10.1002/ana.23832
Language: English
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
UCL classification: UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Motor Neuroscience and Movement Disorders
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Internal Medicine
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > UCL Medical School
URI: http://discovery.ucl.ac.uk/id/eprint/1386494
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