{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:23:23Z","timestamp":1791289403376,"version":"4.3.0"},"reference-count":23,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,4,17]],"date-time":"2013-04-17T00:00:00Z","timestamp":1366156800000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2013,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genome\u2010wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow\u2010up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of <jats:italic>TUBB4<\/jats:italic> mRNA were determined by quantitative real\u2010time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The disease\u2010causing gene was mapped to a 23cM region on chromosome 19p13.3\u2010p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the <jats:italic>TUBB4<\/jats:italic> (tubulin beta\u20104; Arg2Gly) gene as the likely cause of disease. Sequencing of <jats:italic>TUBB4<\/jats:italic> 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 <jats:italic>TUBB4<\/jats:italic> mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>A mutation in <jats:italic>TUBB4<\/jats:italic> causes DYT4 dystonia in this Australian family with so\u2010called whispering dysphonia, and other mutations in <jats:italic>TUBB4<\/jats:italic> 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\u2013545<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.23829","type":"journal-article","created":{"date-parts":[[2012,12,14]],"date-time":"2012-12-14T00:57:41Z","timestamp":1355446661000},"page":"537-545","source":"Crossref","is-referenced-by-count":132,"title":["Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the <i>TUBB4<\/i> gene"],"prefix":"10.1002","volume":"73","author":[{"given":"Katja","family":"Lohmann","sequence":"first","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Wilcox","sequence":"additional","affiliation":[{"name":"Department of Neurology Flinders Medical Centre Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susen","family":"Winkler","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of L\u00fcbeck L\u00fcbeck 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