title: Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wilcox
authors.forename: Susen
authors.initials: S
authors.lastname: Winkler
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rakovic
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Björn
authors.initials: B
authors.lastname: Arns
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.forename: Justus
authors.initials: J
authors.lastname: Groen
authors.forename: Meike
authors.initials: M
authors.lastname: Kasten
authors.forename: Norbert
authors.initials: N
authors.lastname: Brüggemann
authors.forename: Johann
authors.initials: J
authors.lastname: Hagenah
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmidt
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.forename: Kishore R
authors.initials: KR
authors.lastname: Kumar
authors.forename: Katja
authors.initials: K
authors.lastname: Zschiedrich
authors.forename: Daniel
authors.initials: D
authors.lastname: Alvarez-Fischer
authors.forename: Eckart
authors.initials: E
authors.lastname: Altenmüller
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kostic
authors.forename: Kristina
authors.initials: K
authors.lastname: Simonyan
authors.forename: Marc
authors.initials: M
authors.lastname: Agzarian
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.forename: Antonius P M
authors.initials: AP
authors.lastname: Langeveld
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.forename: Marina A J
authors.initials: MA
authors.lastname: Tijssen
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
mesh_terms: D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004252:DNA Mutational Analysis; D004422:Dystonia Musculorum Deformans / Q000235:genetics* / Q000503:physiopathology; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D012720:Severity of Illness Index; D014404:Tubulin / Q000235:genetics*; D014832:Voice Disorders / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology
chemical_list: C582076:TUBB4A protein, human; D014404:Tubulin