GCH1

GTP cyclohydrolase 1

4 disorders 2 causative 1 untyped 1 no genetic record 14q22.2 gene with protein product

HGNC:4193 Monarch NCBI Gene 2643 ENSG00000131979 UniProt P30793 OMIM 600225

Previous symbols: GCH, DYT5, DYT14. Aliases: GTPCH1, DYT5a.

Normal function · from ai-gene-review (P30793, commit 79fe13b38970) · AI-generated, not KB evidence

GCH1 encodes GTP cyclohydrolase 1 (GTPCH1, EC 3.5.4.16), the first and rate-limiting enzyme in the de novo biosynthesis of tetrahydrobiopterin (BH4). GTPCH1 catalyzes the conversion of GTP to 7,8-dihydroneopterin triphosphate, releasing formate and pyrophosphate. The enzyme requires zinc for catalytic activity and functions as a homodecameric complex (dimer of pentamers). BH4 is an essential cofactor for aromatic amino acid hydroxylases (phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase) involved in neurotransmitter synthesis, and for all nitric oxide synthase isoforms. Mutations in GCH1 cause dopa-responsive dystonia (DRD/DYT5) and BH4-deficient hyperphenylalaninemia. Recent evidence also implicates GCH1/BH4 in ferroptosis suppression through its radical-trapping antioxidant function.

The primary molecular function of GCH1 is GTP cyclohydrolase I activity (EC 3.5.4.16), catalyzing the conversion of GTP to 7,8-dihydroneopterin triphosphate as the first and rate-limiting step in de novo tetrahydrobiopterin (BH4) biosynthesis. GTPCH1 is primarily localized in the cytosol and requires zinc for catalytic activity. BH4 is a critical cofactor for aromatic amino acid hydroxylases (PAH, TH, TPH) and all nitric oxide synthase isoforms.

molecular function: GTP cyclohydrolase I activity · directly involved in: tetrahydrobiopterin biosynthetic process · locations: cytosol

In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

Disorder	Relationship	Where the gene appears
Disorder of Catecholamine Synthesis	causative germline	mechanism: BH4 Cofactor Deficiency subtype: Autosomal recessive GTP cyclohydrolase I deficiency scoped to subtype: Autosomal recessive GTP cyclohydrolase I deficiency
Tetrahydrobiopterin Deficiency	causative	mechanism: BH4 Biosynthesis and Regeneration Gene Defect subtype: GTPCH Deficiency scoped to subtype: GTPCH Deficiency
Autosomal Dominant Dopa-Responsive Dystonia	untyped Autosomal dominant pathogenic variants germline	mechanism: GCH1 Haploinsufficiency and GTPCH1 Deficiency scoped to subtype: GCH1-related GTPCH1-deficient DRD
Dopa-Responsive Dystonia	no genetic record	mechanism: BH4 Cofactor Limitation

ClinGen gene–disease validity · snapshot 2026-10-03 · matched to entries by MONDO

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

ClinGen disease	MOI	Classification	dismech entry
GTP cyclohydrolase I deficiency MONDO:0100184	SD	Definitive 2020-12-11	Disorder of Catecholamine Synthesis causative

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.