Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function

Autor(es):Mostrar menos -

dos Santos, Camila Oliveira ^{[1, 2]} ; Masuho, Ikuo ^[3] ; da Silva-Junior, Francisco Pereira ^[4] ; Barbosa, Egberto Reis ^[4] ; Cesar Azevedo Silva, Sonia Maria ^{[1, 5]} ; Borges, Vanderci ^[1] ; Ferraz, Henrique Ballalai ^[1] ; Guimaraes Rocha, Maria Sheila ^[6] ; Papaterra Limongi, Joao Carlos ^[4] ; Martemyanov, Kirill A. ^[3] ; Aguiar, Patricia de Carvalho ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Neurol & Neurosurg, Sao Paulo, SP - Brazil

^[2] Hosp Israelita Albert Einstein, Albert Einstein 627, Bloco A, 2SS IIEP, BR-05652900 Sao Paulo, SP - Brazil

^[3] Scripps Res Inst, Dept Neurosci, Jupiter, FL - USA

^[4] Univ Sao Paulo, Dept Neurol, Sao Paulo, SP - Brazil

^[5] Hosp Servidor Publ Estadual, Sao Paulo, SP - Brazil

^[6] Hosp Santa Marcelina Sao Paulo, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF NEUROLOGY; v. 263, n. 4, p. 665-668, APR 2016.
• Citações Web of Science: 6

Resumo

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 G alpha(olf) 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 G alpha(olf) 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 G alpha(olf) loss of function. (AU)

• Processo FAPESP: 13/09867-7 - Padronização e análise molecular do gene GCH1 na pesquisa de distonia dopa-responsiva
• Beneficiário: Camila Oliveira dos Santos Alves
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 10/19206-0 - Rede brasileira para o estudo das distonias
• Beneficiário: Patrícia Maria de Carvalho Aguiar
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 14/17128-2 - Rede brasileira para o estudo das distonias: estudo de variantes em novos genes (GNAL, CIZ1, ANO3, e TUBB4) em pacientes com distonia idiopática
• Beneficiário: Patrícia Maria de Carvalho Aguiar
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/18202-3 - Rede Brasileira para o Estudo das Distonias
• Beneficiário: Camila Oliveira dos Santos Alves
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico