GCH1

Chr 14

GTP cyclohydrolase 1

Also known as: DYT14, DYT5, DYT5a, GCH, GTP-CH-1, GTPCH1, HPABH4B

NCBI Gene: 2643 ENSG00000131979 UniProt: P30793

The protein is GTP cyclohydrolase I, the rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis that converts GTP to 7,8-dihydroneopterin triphosphate, with BH4 serving as an essential cofactor for aromatic amino acid hydroxylases and nitric oxide synthases. Loss-of-function mutations cause dopa-responsive dystonia (autosomal dominant) and BH4-deficient hyperphenylalaninemia (autosomal recessive). The pathogenic mechanism involves loss of enzyme function leading to BH4 deficiency and subsequent impairment of dopamine and other neurotransmitter synthesis.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the GTP cyclohydrolase family. The encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate. BH4 is an essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases. Mutations in this gene are associated with malignant hyperphenylalaninemia and dopa-responsive dystonia. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all variants give rise to a functional enzyme. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHyperphenylalaninemia, BH4-deficient, B

UniProtDystonia, dopa-responsive

Clinical highlights

Management implications

Dramatic, sustained response to low-dose levodopa — warrant a diagnostic trial in childhood dystonia.A levodopa trial is warranted in any childhood-onset dystonia — DRD responds dramatically and durably.

GCH1: treatable — levodopa

Gene-disease validity (ClinGen)

GTP cyclohydrolase I deficiency · SDDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

102

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.40

LOEUF

LOF

Mechanism· predicted

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GeneReview available — GCH1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Treatment implicationsTreatable

Dopa-responsive dystonia (Segawa syndrome) / GTP-cyclohydrolase-1 deficiency

A levodopa trial is warranted in any childhood-onset dystonia — DRD responds dramatically and durably.

Dramatic, sustained response to low-dose levodopa — warrant a diagnostic trial in childhood dystonia.

Treatment of choice

levodopa (low-dosesustained response)

Wijemanne & Jankovic 2015, Lancet Neurol. Confirm with a neurologist and current guidelines. Functional class (GOF/LOF) is from published functional/segregation data, never inferred from the variant. As of 2026-07. Curated from the clinical genetics/neurology literature (cited per gene). Decision-support, not prescribing.