Journal
ANNALS OF NEUROLOGY
Volume 73, Issue 4, Pages 546-553Publisher
WILEY-BLACKWELL
DOI: 10.1002/ana.23832
Keywords
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Funding
- Medical Research Council
- Dystonia Medical Research Foundation
- Dystonia Coalition
- National Institute for Health Research (NIHR) UCL/UCLH Biomedical Research Centres funding Scheme
- Wellcome Trust/MRC
- UK Parkinson's Disease Consortium
- Parkinson's Disease Foundation
- GSK
- Boehringer Ingelheim
- Ipsen
- Merz
- Orion Pharma
- Bachmann-Strauss
- Medical Research Council [G0802462, MC_G0901330, MC_PC_09003, G108/638, MR/J004758/1, MC_G1000735, G0802760, G1001253] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10376] Funding Source: researchfish
- Parkinson's UK [G-0907, G-1107] Funding Source: researchfish
- MRC [MC_G1000735, G0802462, MC_G0901330, G0802760, MC_PC_09003, G108/638, G1001253, MR/J004758/1] Funding Source: UKRI
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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 -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. Ann Neurol 2013;73:546-553
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