GCH1 – Parkinson Disease Risk and Clinical Spectrum

GCH1 encodes GTP cyclohydrolase I, the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis essential for dopamine production in nigrostriatal neurons. Initially implicated in autosomal dominant dopa-responsive dystonia (DRD), heterozygous and common regulatory variants in GCH1 have been investigated for association with Parkinson disease (PD). Genetic screens and case-control studies have assessed the frequency and impact of GCH1 variants in PD cohorts.

Case-control sequencing of GCH1 in 1,113 PD patients versus 1,111 controls identified a significant burden of rare, DRD-related GCH1 variants in PD (three variants in five patients, none in controls) supporting a risk role (PMID:30314816). A common 3′UTR variant (C+243T) also modulates BH4 levels and autonomic function, implicating regulatory mechanisms in PD susceptibility (PMID:17717598).

In a British kindred carrying the DRD-linked missense variant c.5A>G (p.Glu2Gly), five carriers were identified, of whom two presented with adult-onset PD, demonstrating pleiotropic effects and familial segregation (PMID:25634433). Across PD cohorts, at least four rare coding variants—c.206C>T (p.Pro69Leu), c.690G>T (p.Met230Ile), c.671A>G (p.Lys224Arg), c.646C>T (p.Arg216Ter)—have been reported in PD patients, substantiating a variant spectrum overlapping DRD and PD (PMID:30314816).

Functional assays reveal that GCH1 missense and noncoding variants reduce enzyme expression or activity, leading to decreased BH4 and impaired dopamine synthesis. The C+243T 3′UTR variant reduces reporter expression in vitro, while GCH1 missense mutations demonstrate loss-of-function in yeast and mammalian cells, consistent with a haploinsufficiency mechanism (PMID:17717598; PMID:39026821).

However, targeted deep sequencing in 509 late-onset PD patients and 230 controls found no putatively pathogenic GCH1 coding changes, indicating variant frequency may be population- and age-dependent (PMID:27185167). Similarly, GCH1 rs11158026 showed no association with PD in a Han Chinese cohort, highlighting the need for larger multiethnic studies (PMID:26804608).

Overall, GCH1 exhibits a Moderate level of evidence for PD risk. Rare, DRD-related GCH1 variants and regulatory alleles contribute to PD susceptibility through reduced BH4 synthesis. Additional large-scale sequencing and functional studies are warranted to clarify population-specific effects.

Key Take-home: GCH1 pathogenic and regulatory variants confer a moderate increase in Parkinson disease risk via BH4-dependent dopamine synthesis deficiency, meriting consideration in genetic testing and risk assessment strategies.

References

• Neurobiology of aging • 2019 • Common and rare GCH1 variants are associated with Parkinson's disease PMID:30314816
• Parkinsonism & related disorders • 2015 • Novel GCH1 variant in Dopa-responsive dystonia and Parkinson's disease PMID:25634433
• The Journal of clinical investigation • 2007 • Discovery of common human genetic variants of GTP cyclohydrolase 1 (GCH1) governing nitric oxide, autonomic activity, and cardiovascular risk PMID:17717598
• Parkinsonism & related disorders • 2016 • Low frequency of GCH1 and TH mutations in Parkinson's disease PMID:27185167
• Neurobiology of aging • 2016 • Association of GCH1 and MIR4697, but not SIPA1L2 and VPS13C polymorphisms, with Parkinson's disease in Taiwan PMID:26804608

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