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Abstract <p>Mutations in the guanosine triphosphate cyclohydrolase-1 (<i>GCH1</i>) gene are the most common cause of hereditary dopa-responsive dystonia (DRD), designated as DYT5a (OMIM #128230). The most typical manifestations of this form of the disease include childhood manifestations in the form of focal dystonia (mainly in the foot), diurnal fluctuations, and sometimes a combination of dystonia with mild parkinsonism. The main feature of DYT5a is the good and sustained efficacy of treatment with a low dose of L‑Dopa. At the same time, the rarity of the disease itself and a significant variety of mutations and clinical heterogeneity, including atypical manifestations, do not allow establishing clear genotypic correlations, complicating its early diagnosis. In this regard, identification of pathogenic variants causing the development of DYT5a, studies of clinical and genetic features of various genetic variants of the disease and their prevalence in populations are relevant. In this report, we present information on a new missense variant in the <i>GCH1</i> gene—c.710A&gt;G (p.Asp237Gly) (NM_000161.3), identified as a result of whole-genome sequencing in a family with an autosomal dominant form of dystonia from the Republic of Bashkortostan. On the basis of bioinformatic analysis, this nucleotide variant is interpreted as having a damaging effect. In the heterozygous state, it was identified in two affected family members and in two close relatives without signs of dystonia. The clinical picture of the disease in both affected women from this family corresponds to the classical DYT5a. This variant was not detected in the control population samples of healthy individuals. No other pathogenic variants in genes known for dystonia were detected in patients from the examined family. On the basis of the totality of data, we assume that the missense variant c.710A&gt;G (p.Asp237Gly) in the <i>GCH1</i> gene is most likely the cause of the disease and can be further classified as “pathogenic” characterized by incomplete penetrance, which requires additional functional studies.</p>

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A Novel Missense Variant in the GCH1 Gene Identified in Patients with Dopa-Responsive Dystonia

  • 期刊论文

  • 发表日期：

    2026年2月1日

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  • I. M. Khidiyatova,
  • A. S. Karunas,
  • R. A. Ibatullin,
  • K. A. Federiaev,
  • A. A. Akhmetshin,
  • L. A. Smakova,
  • V. L. Akhmetova,
  • N. N. Khusnutdinova,
  • O. I. Klimchuk,
  • E. K. Khusnutdinova

摘要

Abstract

Mutations in the guanosine triphosphate cyclohydrolase-1 (GCH1) gene are the most common cause of hereditary dopa-responsive dystonia (DRD), designated as DYT5a (OMIM #128230). The most typical manifestations of this form of the disease include childhood manifestations in the form of focal dystonia (mainly in the foot), diurnal fluctuations, and sometimes a combination of dystonia with mild parkinsonism. The main feature of DYT5a is the good and sustained efficacy of treatment with a low dose of L‑Dopa. At the same time, the rarity of the disease itself and a significant variety of mutations and clinical heterogeneity, including atypical manifestations, do not allow establishing clear genotypic correlations, complicating its early diagnosis. In this regard, identification of pathogenic variants causing the development of DYT5a, studies of clinical and genetic features of various genetic variants of the disease and their prevalence in populations are relevant. In this report, we present information on a new missense variant in the GCH1 gene—c.710A>G (p.Asp237Gly) (NM_000161.3), identified as a result of whole-genome sequencing in a family with an autosomal dominant form of dystonia from the Republic of Bashkortostan. On the basis of bioinformatic analysis, this nucleotide variant is interpreted as having a damaging effect. In the heterozygous state, it was identified in two affected family members and in two close relatives without signs of dystonia. The clinical picture of the disease in both affected women from this family corresponds to the classical DYT5a. This variant was not detected in the control population samples of healthy individuals. No other pathogenic variants in genes known for dystonia were detected in patients from the examined family. On the basis of the totality of data, we assume that the missense variant c.710A>G (p.Asp237Gly) in the GCH1 gene is most likely the cause of the disease and can be further classified as “pathogenic” characterized by incomplete penetrance, which requires additional functional studies.