Role of Gα(olf) in familial and sporadic adult-onset primary dystonia

Abstract

The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ~10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.

ADCY5 -related dyskinesia

“…Altered striatal dopamine signaling is one hypothesis for various forms of dystonia, including defects in the biosynthesis or transport of dopamine, 20 DYT1 Torsin A-related dystonia, 21,22 DYT25 GNAL-related dystonia, 23,24 and adult-onset focal dystonia. 25 ADCY5 is the principal adenylate cyclase integrating signals from multiple receptors including D1 and D2 striatal dopamine receptors.…”

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

“…Dystonia remained focal in about half of these patients, with the rest showing spread to contiguous regions (e.g., developing segmental dystonia). Subsequent reports [45][46][47][48][49] demonstrated yet additional GNAL mutations in patients with a similar clinical phenotype (i.e., adult-onset, cervical predominant). While the age at onset is typically in the fifth to sixth decade, GNAL mutations lead to a rather broad range of age at onset, spanning from age 7 to 54 years.…”

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.…”

“…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). GNAL encodes the stimulatory subunit of a G-protein that is involved in dopamine signaling (27) and is expressed in medium spiny neurons in the striatum.…”