Mutations in GNAL cause primary torsion dystonia

Abstract

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1)3, THAP1 (DYT6)4, and CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutation resulting in premature stop codon in one family and a missense p.V137M mutation in the other. Screening of GNAL in 39 PTD families, revealed six additional novel mutations in this gene. Impaired function of several of the mutations was shown by bioluminescence resonance energy transfer (BRET) assays.

The genetics of the dystonias – a review based on the new classification of the dystonias

“…The family initially reported by Bressman et al 29 and the cases reported to date suggest that this dystonia, which was designated DYT25, has a phenotype that is initially predominantly cervical with a tendency to present as craniocervical dystonia with spasmodic dysphonia with or without generalization 28 .…”

“…Fuchs et al 28 reported twenty-eight patients with dystonia in eight families, including the family initially described by Bressman et al 29 in 1994. They confirmed that mutations in the GNAL gene were the cause of dystonia in these patients.…”

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

“…Finally, in 2013, two groups reported that mutations in the GNAL gene could cause adult onset primary dystonia (25, 26) with a strong predilection for the cervical region. Cervical dystonia was observed in 93% and spread to other sites in half of cases (25). According to the report of the first group, six of 39 families screened (15%) had mutations in this gene, but the second group found only three patients with mutations among 760 persons screened (26).…”

“…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.…”

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

“…Yet these genes cause isolated dystonia that is primarily of childhood-onset; isolated dystonia much more commonly begins in adulthood. Against this backdrop, the identification of GNAL mutations (DYT25) is particularly exciting [44], being the first gene linked to adult-onset focal/ segmental dystonia-a condition commonly seen by movement disorders neurologists. Indeed, the discovery of this gene will allow studies exploring potential links between childhood-and adult-onset dystonia-an important question in dystonia research.…”