<i>GCH1</i> ve Dopa-Responsive Dystonia'lı bir Çin Ailesinde Klinik Heterojenitenin 5'-Çeviren Bölgesinde Patojenik Varyant.

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BackgroundVariants in the GCH1 gene, encoding guanosine triphosphate cyclohydrolase, are associated with dopa-responsive dystonia (DRD) and are considered risk factors for parkinson's disease.MethodsComprehensive neurological assessments documented motor and non-motor symptoms in a Chinese family affected by DRD. Whole-exome sequencing (WES) was employed to identify potential mutations, with key variants confirmed by Sanger sequencing and analyzed for familial co-segregation.ResultsThe proband, a 50-year-old woman with a 10-year history of limb rigidity, abnormal posture, and a 23-year history of neck deviation, showed significant symptom improvement with levodopa treatment. Family evaluation revealed similar motor symptoms in four additional affected members, all responding well to levodopa. WES identified a GCH1 variant (NM_000161.3: c.-22C > T) in the 5'-untranslated region (5' UTR) in four symptomatic individuals (excluding deceased II-3). This variant likely affects translation by introducing an upstream initiation codon and open reading frame (uORF), leading to decreased BH4 levels and disrupted dopamine synthesis.DiscussionThis study reports a pathogenic variant in the 5' UTR of GCH1 in a family with DRD, underscoring the phenotypic heterogeneity associated with this locus.HighlightsA non-coding variant (c.-22C > T) in the 5' UTR of the GCH1 gene is identified in a Chinese family with DRD.The findings reveal significant clinical heterogeneity within the family, highlighting the complex genotype-phenotype relationship.

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