Mutations in the autoregulatory domain of β‐tubulin 4a cause hereditary dystonia

Abstract

Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.12-13. Exome sequencing in 2 cousins identified a single cosegregating mutation (p.R2G) in the β-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the β-tubulin autoregulatory MREI (methionine–arginine–glutamic acid–isoleucine) domain, highly expressed in the central nervous system, and extensive in vitro work has previously demonstrated that substitutions at residue 2, specifically R2G, disrupt the autoregulatory capability of the wild-type β-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis.

TUBB4A de novo mutations cause isolated hypomyelination

“…2,3 In DYT4, an autosomal dominant mutation (c.4C.G [p.Arg2Gly]) in TUBB4A (NM_006087.2) was identified in patients presenting with a "whispering" dysphonia, generalized dystonia, and gait ataxia, but normal MRI features. 2 In H-ABC, a cohort of 11 individuals were found to have a common de novo mutation at c.745G.A (p.Asp249Asn) in TUBB4A.…”

“…2,3 In DYT4, an autosomal dominant mutation (c.4C.G [p.Arg2Gly]) in TUBB4A (NM_006087.2) was identified in patients presenting with a "whispering" dysphonia, generalized dystonia, and gait ataxia, but normal MRI features. 2 In H-ABC, a cohort of 11 individuals were found to have a common de novo mutation at c.745G.A (p.Asp249Asn) in TUBB4A. 3 H-ABC is a rare leukodystrophy diagnosed on the basis of distinctive MRI findings including hypomyelination, cerebellar atrophy, and absence or disappearance of the putamen at an early age.…”

Epilepsy in Multigene Tubulin Family Mutations

“…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].…”

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

“…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.…”

“…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).…”