Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene
Article first published online: 17 APR 2013
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 73, Issue 4, pages 537–545, April 2013
How to Cite
Lohmann, K., Wilcox, R. A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.-S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Brüggemann, N., Hagenah, J., Schmidt, A., Kaiser, F. J., Kumar, K. R., Zschiedrich, K., Alvarez-Fischer, D., Altenmüller, E., Ferbert, A., Lang, A. E., Münchau, A., Kostic, V., Simonyan, K., Agzarian, M., Ozelius, L. J., Langeveld, A. P. M., Sue, C. M., Tijssen, M. A. J. and Klein, C. (2013), Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann Neurol., 73: 537–545. doi: 10.1002/ana.23829
- Issue published online: 21 MAY 2013
- Article first published online: 17 APR 2013
- Accepted manuscript online: 13 DEC 2012 04:42AM EST
- Manuscript Accepted: 30 NOV 2012
- Manuscript Revised: 13 NOV 2012
- Manuscript Received: 19 SEP 2012
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.
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.
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.
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