GNAL mutations cause adult-onset primary dystonia
Forskningsoutput: Tidskriftsbidrag › Publicerat konferensabstract
OBJECTIVE: Identification of the causal mutation in an African-American family with adult-onset primary dystonia. BACKGROUND: The vast majority of patients with dystonia are adults with primary focal or segmental anatomical distributions. Familial and sporadic dystonia appear to share the same genetic etiological background. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large pedigrees suited for linkage analysis are uncommon. In previous work, we excluded THAP1 and TOR1A mutations in an African-American family with clinical phenotypes that included cervical, laryngeal and hand-forearm dystonia. DESIGN/METHODS: Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in order to identify the causal mutation (GNAL, c.913G>T) in our African-American family with dystonia. High resolution melting and Sanger sequencing were used to screen 768 additional subjects with primary cervical or segmental dystonia for sequence variants in GNAL. RESULTS: The missense mutation in GNAL (c.913G>T, p.V305F) was found to co-segregate with dystonia in our African-American pedigree. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) is highly expressed in the olfactory bulb, striatum and cerebellar Purkinje cells. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. Screening identified two additional pedigrees with GNAL mutations (c.822-823insA [p.R275T∗13] and c.964C>T [p.R322∗]). None of these sequence variants were found in 760 controls. CONCLUSIONS: Mutations in GNAL are causally-associated with adult-onset primary cervical and segmental dystonia. The prominent expression of Gα(olf) in striatum and cerebellar Purkinje cells points to potential sites of functional pathology in primary dystonia.
|Enheter & grupper|
Ämnesklassifikation (UKÄ) – OBLIGATORISK
|Status||Published - 2013 feb 12|
|Peer review utförd||Ja|