title: Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function.
abstract: GNAL was identified as a cause of dystonia in patients from North America, Europe and Asia. In this study, we aimed to investigate the prevalence of GNAL variants in Brazilian patients with dystonia. Ninety-one patients with isolated idiopathic dystonia, negative for THAP1 and TOR1A mutations, were screened for GNAL variants by Sanger sequencing. Functional characterization of the Gαolf protein variant was performed using the bioluminescence resonance energy transfer assay. A novel heterozygous nonsynonymous variant (p. F133L) was identified in a patient with cervical and laryngeal dystonia since the third decade of life, with no family history. This variant was not identified in healthy Brazilian controls and was not described in 63,000 exomas of the ExAC database. The F133L mutant exhibited significantly elevated levels of basal BRET and severely diminished amplitude of response elicited by dopamine, that both indicate substantial functional impairment of Gαolf in transducing receptor signals, which could be involved in dystonia pathophysiology. GNAL mutations are not a common cause of dystonia in the Brazilian population and have a lower prevalence than THAP1 and TOR1A mutations. We present a novel variant that results in partial Gαolf loss of function.
authors.affiliation: Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil.|Hospital Israelita Albert Einstein, Av Albert Einstein 627, Bloco A, 2SS IIEP, Sao Paulo, SP, 05652-900, Brazil.
authors.forename: Camila Oliveira
authors.initials: CO
authors.lastname: Dos Santos
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Masuho
authors.affiliation: Department of Neurology, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Francisco Pereira
authors.initials: FP
authors.lastname: da Silva-Júnior
authors.affiliation: Department of Neurology, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Egberto Reis
authors.initials: ER
authors.lastname: Barbosa
authors.affiliation: Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil.|Hospital do Servidor Público Estadual, Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Sonia Maria Cesar Azevedo
authors.initials: SM
authors.lastname: Silva
authors.affiliation: Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil.
authors.forename: Vanderci
authors.initials: V
authors.lastname: Borges
authors.affiliation: Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil.
authors.forename: Henrique Ballalai
authors.initials: HB
authors.lastname: Ferraz
authors.affiliation: Hospital Santa Marcelina Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Maria Sheila Guimarães
authors.initials: MS
authors.lastname: Rocha
authors.affiliation: Department of Neurology, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: João Carlos Papaterra
authors.initials: JC
authors.lastname: Limongi
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
authors.affiliation: Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, Sao Paulo, SP, Brazil. patriciamc@einstein.br.|Hospital Israelita Albert Einstein, Av Albert Einstein 627, Bloco A, 2SS IIEP, Sao Paulo, SP, 05652-900, Brazil. patriciamc@einstein.br.
authors.forename: Patricia
authors.identifier: http://orcid.org/0000-0003-2957-9573
authors.initials: P
authors.lastname: de Carvalho Aguiar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics*; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D055815:Young Adult
chemical_list: D044385:GTP-Binding Protein alpha Subunits; C084618:olfactory G protein subunit alpha olf
keywords: DYT25; Dystonia; GNAL; Genetics; Gαolf
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