Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the <i>TUBB4</i> gene

Lohmann, Katja; Wilcox, Robert G.; Winkler, Susen; Ramı́rez, Alfredo; Raković, Aleksandar; Park, Jin-Sung; Arns, Björn; Lohnau, Thora; Groen, Justus L.; Kasten, Meike; Brüggemann, Norbert; Hagenah, Johann; Schmidt, Alexander; Kaiser, Frank J.; Kumar, Kishore R.; Zschiedrich, Katja; Alvarez‐Fischer, Daniel; Altenmüller, Eckart; Ferbert, A.; Lang, Anthony E.; Münchau, Alexander; Kostić, Vladimir; Simonyan, Kristina; Agzarian, Marc; Ozelius, Laurie J.; Langeveld, Antonius P. M.; Sue, Carolyn M.; Tijssen, Marina A. J.; Klein, Christine

doi:10.1002/ana.23829

Cited by 138 publications

(133 citation statements)

References 23 publications

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“…In recent years, a specific phenotype has been described in association with mutations in the TUBB4 gene, characterized by whispering dysphonia, generalized dystonia, ataxic gait (hobby horse), but without neuroradiological and defined dystonia type 4 (DYT4) [41,42]. A rare form of leukoencephalopathy, chacterized by hypomielination with atrophy of the basal ganglia and cerebellum (H-ABC), has been described also associated to mutations of the TUBB4A gene [18][19][20][21], supporting the hypothesis that tubulin genes have subtle, but yet distinct roles in microtubular dynamics and functions, according to cell type and neurodevelopmental time points [9].…”

Section: Tubulin β-4a (Tubb4a) Gene [Orpha98805 Omim 602662]mentioning

confidence: 99%

Epilepsy in Multigene Tubulin Family Mutations

Romaniello¹,

Borgatti²

2015

J Neurol Neurophysiol

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Mutations in α-and β-tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation, and axon guidance and maintenance. Motor and language developmental disorders, cognitive impairment and epilepsy are the main clinical associated symptoms. Frequency and severity of these disorders are largely related with the involvement of specific tubulin genes and their functions.The present study summarizes all the published data on tubulin family gene mutations and the associated clinical phenotype in order to define epilepsy recurrence and its characteristics.Mutations disrupting the stability of microtubules, mainly mechanisms involving neuronal migration and organization, may play an important role in epileptogenicity. Moreover, since mutations in the α-and β-tubulin genes are responsible for a large spectrum of cortical and brain malformations, they do not show a high specificity and correlation with an epileptic phenotype unlike other MCDs-related genes. Usually seizures start early (in the first year of life) and they are more often generalized (infantile spasms, tonic, tonic-clonic) as expression of a diffuse cortical maldevelopment.Mutations in the TUBA1A gene, causing various degrees of agyria-pachigyria spectrum, classical lissencephaly or polymicrogyria, represent among tubulin genes, the major responsible of epilepsy (about 50% of the cases).Disorders of cortical development as polymicrogyria, various types of gyral disorganization and schizencephaly were also described in cases carrying TUBB2B gene mutations showing epilepsy in the 40%.As far as mutations in the TUBB4A gene are concerned, despite the brain phenotype is represented by a form of leukoencephalopathy characterized by hypomielination with atrophy of the basal ganglia and cerebellum and not by MCDs, epilepsy is present in about 40% of the mutated subjects.On the contrary, mutations in the TUBB3 gene cause epilepsy only in 15% of cases, while seizures have never been described in association with TUBB gene.

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Section: Tubulin β-4a (Tubb4a) Gene [Orpha98805 Omim 602662]mentioning

confidence: 99%

Epilepsy in Multigene Tubulin Family Mutations

Romaniello¹,

Borgatti²

2015

J Neurol Neurophysiol

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“…Five descriptors are utilized to specify the clinical features axis: age at onset, body distribution, temporal pattern, coexistence of other movement disorders, and coexistence of other neurological or systemic manifestations. Age at onset is divided into infancy (0-2 years), childhood (3-12 years), adolescence (13-20 years), early adulthood (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), and late adulthood (>40 years). Body distribution is, as in earlier classifications, divided into focal, segmental, multifocal, generalized, and hemidystonia.…”

Section: Definition and Classificationmentioning

confidence: 99%

“…Mutations in the TUBB4a gene were found in a large English-Australian family that has the fully penetrant adductor spasmodic dysphonia (DYT4-dystonia) with juvenile to adult onset, occasional generalization, and sometimes alcohol benefit (21,22). Three different genes have been found in families with mainly adolescent to adult onset of cervical focal or segmental dystonia (involvement of larynx or arm, Table 1).…”

Section: Genetics and Pathophysiologymentioning

confidence: 99%

Dystonia - new advances in classification, genetics, pathophysiology and treatment

Skogseid

2014

Acta Neurol Scand

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“…These results suggest a possibility that other dystonia genes, especially early-onset genes, are affecting the same signaling pathway as TOR1A/DYT1. We will test orthologs of other early onset dystonia genes including TUBB4/DYT4 [27] (three fly homologs, βTub56D, βTub60D, and βTub85D), Thap1/DYT6 [28] (two fly homologs, CG14965 and CG10431), and PRKRA/DYT16 [29] (one fly ortholog, loqs). We will also test RNAi line for orthologs of newly identified dystonia genes when they become known.…”

Section: (D) Other Dystonia Genesmentioning

confidence: 99%

A Novel Locomotion-based Validation Assay for Candidate Drugs Using Drosophila DYT1 Disease Model

Ito¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERMassachusetts General Hospital Charlestown, Massachusetts 02129 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTWe have established fly lines expressing a mutant form of human torsinA (torsinAΔE) in fly brains. We have shown that (1) human torsinAΔE protein is expressed in fly brains; (2) expression of human torsinAΔE dominantly suppresses larval locomotion and GTPC cyclrohydolase protein levels; (3) supplementation of dopamine can partially rescue the locomotion defects of Drosophila larvae caused by the expression of human torsinAΔE. These results demonstrated that human torsinA can cause locomotion defects and reduction of GTP cyclohydrolase proteins very similar to the phenotypes in dtorsin-null larval brains. These results suggested that we can study the molecular defects of human torsinAΔE using our fly model system. We have submitted a manuscript describing our results. We have conducted preliminary RNAi screen to identify modifiers of dtorsin-null locomotion defect phenotype. Our preliminary results suggest that (1) dopamine signaling pathway; (2) RNP transport pathway; (3) axon guidance pathway; and (4) other early-onset dystonia genes as candidates for modifiers. These RNAi screen will be very useful for identifying potential therapeutic targets of early-onset dystonia patients.

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

Cited by 138 publications

References 23 publications

Epilepsy in Multigene Tubulin Family Mutations

Epilepsy in Multigene Tubulin Family Mutations

Dystonia - new advances in classification, genetics, pathophysiology and treatment

A Novel Locomotion-based Validation Assay for Candidate Drugs Using Drosophila DYT1 Disease Model

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