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

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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.

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Study funding: Sao Paulo Research Foundation (FAPESP) Grants # 2010/19206-0 (PCA); 2011/18202-3 (COS); 2013/09867-7(COS), 2014/17128-2(PCA) NIH grant NS081282 (KAM). The authors thank all patients and their families, the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at

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Correspondence to Patricia de Carvalho Aguiar.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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This study was approved by the Institutional Review Boards and all subjects provided informed written consent.

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dos Santos, C.O., Masuho, I., da Silva-Júnior, F.P. et al. Screening of GNAL variants in Brazilian patients with isolated dystonia reveals a novel mutation with partial loss of function. J Neurol 263, 665–668 (2016).

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