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. 2013 Jun 15;22(12):2510-9.
doi: 10.1093/hmg/ddt102. Epub 2013 Feb 27.

Role of Gα(olf) in Familial and Sporadic Adult-Onset Primary Dystonia

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Free PMC article

Role of Gα(olf) in Familial and Sporadic Adult-Onset Primary Dystonia

Satya R Vemula et al. Hum Mol Genet. .
Free PMC article

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.

Figures

Figure 1.
Figure 1.
Family pedigrees. Filled symbols, definitely affected. Half-filled symbols, probably affected. Symbols with central dots, unaffected carriers. Arrows, probands. GNAL genotypes: wild-type (+/+) and heterozygous mutant (+/−). The genotypes of three subjects from Family B have recently been reported (13).
Figure 2.
Figure 2.
Organization of GNAL gene, transcripts and full-length protein. (A) Structure of GNAL on Chr 18p presented in the 5′ to 3′ direction showing the location of four identified mutations in probands with dystonia. (B) The long and major isoforms of GNAL differ at Exon 1. (C) Missense mutations in highly conserved regions of Gα(olf) are shown in relationship to GTP binding domains (G1–G5). (D) The three Gα(olf) amino acids altered by missense mutations in GNAL show conservation in mammals (chimpanzees, marmosets, pigs, mice, rats, hamsters, rabbits, dogs, galagos, elephants, cows, and opossums) non-mammalian vertebrates (chickens, zebrafish, and frogs) and invertebrates (roundworms and fruit flies).
Figure 3.
Figure 3.
Immunohistochemical localization of Gα(olf) in P14 and adult rat brain. (A) Para-sagittal rat brain section. OB, olfactory bulb, ST, striatum. TH, thalamus. (B1–6), Double-label fluorescence immunohistochemistry for simultaneous detection of Purkinje cell marker calbindin (red), TH or ChAT (red) with Gα(olf) (green) in P14 (B1-3) and adult (B4-6) rat brain. Gα(olf) -IR was present in ChAT-positive cholinergic neurons in striatum (C1–6) and TH-positive dopaminergic neurons in substantia nigra (D1–6). (E1–8), Triple-label fluorescent immunohistochemistry for simultaneous detection of PMCA4 (green), CRH-RI/II (red) and Gα(olf) (blue) in P14 (E1–4) and adult (E5–8) rat brains. Scale bar, 2 mm for A and 100 μm for the remaining images.

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