Mutations in the autoregulatory domain of ß-tubulin 4a cause hereditary dystonia.
Ann Neurol
; 73(4): 546-53, 2013 Apr.
Article
em En
| MEDLINE
| ID: mdl-23424103
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 ß-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the ß-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 ß-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tubulina (Proteína)
/
Predisposição Genética para Doença
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Distúrbios Distônicos
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Animals
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Female
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Humans
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Male
/
Middle aged
País/Região como assunto:
Europa
/
Oceania
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article