Pathogenic Variant in the 5'-Untranslated Region of <i>GCH1</i> and Clinical Heterogeneity in a Chinese Family with Dopa-Responsive Dystonia.

Research overview

The text below is the source article’s original abstract under a verified reuse license. cc by

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.

Related topics