Premium
Mutations in the autoregulatory domain of β‐tubulin 4a cause hereditary dystonia
Author(s) -
Hersheson Joshua,
Mencacci Niccolo E.,
Davis Mary,
MacDonald Nicola,
Trabzuni Daniah,
Ryten Mina,
Pittman Alan,
Paudel Reema,
Kara Eleanna,
Fawcett Katherine,
Plagnol Vincent,
Bhatia Kailash P.,
Medlar Alan J.,
Stanescu Horia C.,
Hardy John,
Kleta Robert,
Wood Nicholas W.,
Houlden Henry
Publication year - 2013
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23832
Subject(s) - dystonia , genetics , exome sequencing , biology , exome , mutation , gene , neuroscience
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. Ann Neurol 2013;73:546–553