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

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 ?-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the ?-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 ?-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis.

SUBMITTER: Hersheson J 

PROVIDER: S-EPMC3698699 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature