Hersheson, J; Mencacci, NE; Davis, M; MacDonald, N; Trabzuni, D; Ryten, M; ... Houlden, H; + view all 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; - view fewer (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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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.
|Title:||Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.|
|Additional information:||PMCID: PMC3698699|
|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)
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