Work

Pathogenic Variant in the 5’-Untranslated Region of GCH1 and Clinical Heterogeneity in a Chinese Family with Dopa-Responsive Dystonia

Year: 2025

Type: article

Abstract: Background: Variants in the GCH1 gene, encoding guanosine triphosphate cyclohydrolase, are associated with dopa-responsive dystonia (DRD) and are considered risk factors for parkinson’s disease. Methods: Comprehensive 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. Results: The 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. Discussion: This study reports a pathogenic variant in the 5’ UTR of GCH1 in a family with DRD, underscoring the phenotypic heterogeneity associated with this locus. Highlights A 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.

Source: Tremor and Other Hyperkinetic Movements

DOI: 10.5334/tohm.974

Authors: Yanting Li, Mingqiang Li, Lanqing Liu, Qiying Sun, Guang Yang

Institutions: Central South University, Xiangya Hospital Central South University, First Affiliated Hospital of University of South China, University of South China

Language: English

Topic: Metabolism and Genetic Disorders

Subfield: Clinical Biochemistry

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $800