Journal
ANNALS OF NEUROLOGY
Volume 73, Issue 4, Pages 537-545Publisher
WILEY-BLACKWELL
DOI: 10.1002/ana.23829
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Funding
- Bachmann Strauss Dystonia and Parkinson Foundation
- University of Lubeck (SPP Genetics)
- Hermann and Lilly Schilling Foundation
- Australian Brain Foundation
- National Health and Medical Research Council of Australia
- German Research Foundation
- Brain Foundation
- Dora Lush NHMRC Postgraduate Scholarship
- University Medical Center Giessen and Marburg (UKGM)
- Merz
- Allergan
- Ipsen Pharma
- Eisai
- Deutsche Forschungsgemeinschaft
- European Science Foundation
- Pharm Allergan
- Ipsen
- Merz Pharmaceuticals
- MNT Serbia [175090]
- Novartis
- Alkaloid Skoplje
- Boehringer
- Libra
- Abbott Laboratories
- GlaxoSmithKline
- Pfizer
- Ontario Problem Gambling Research Centre
- Canadian Institutes of Health Research
- Michael J. Fox Foundation
- National Parkinson Foundation
- Prinses Beatrix Fonds Stichting Wetenschapsfonds Dystonie Vereniging STW Technology Society
- dystonia nurse, Ipsen
- European Foundation
- BMBF
- AAN Annual Meeting
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Objective A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. Methods Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. Results The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. Interpretation A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia. Ann Neurol 2013;73:537-545
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