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.
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