Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene

Katja Lohmann, Robert Wilcox, Susen Winkler, Alfredo Ramirez, Aleksandar Rakovic, Jin-Sung Park, Bjorn Arns, Thora Lohnau, Justus Groen, Meike Kasten, Norbert Bruggemann, Johann Hagenah, Alexander Schmidt, Frank Kaiser, Kishore Kumar, Katja Zschiedrich, Daniel Alvarez-Fischer, Eckart Altenmuller, Andreas Ferbert, Anthony LangAlexander Munchau, Vladimir Kostic, Kristina Simonyan, Marc Agzarian, Laurie Ozelius, Antonius Langeveld, Carolyn Sue, Marina Tijssen, Christine Klein

    Research output: Contribution to journalArticle

    92 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)537-545
    Number of pages9
    JournalAnnals of Neurology
    Volume73
    Issue number4
    DOIs
    Publication statusPublished - Apr 2013

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