• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
GCH1 (HGNC:4193) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
GTP cyclohydrolase 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
GCH, DYT5, DYT14
Alias symbols
GTPCH1, DYT5a
%HI
28.56(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.9(Read more about gnomAD pLI score)
LOEUF
0.4(Read more about gnomAD LOEUF score)
Cytoband
14q22.2
Genomic Coordinates
GRCh37/hg19: chr14:55308735-55369544 NCBI Ensembl UCSC
GRCh38/hg38: chr14:54842017-54902826 NCBI Ensembl UCSC
MANE Select Transcript
NM_000161.3 ENST00000491895.7 (Read more about MANE Select)
Function
Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown. {ECO:0000269|PubMed:12176133, ECO:0000269|PubMed:16338639, ECO:0000269|PubMed:17057711, ECO:0000269|PubMed:8068008, ECO:0000269|PubMed:9445252}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-35948
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Assoc. with Reduced Penetrance:
Yes
Studies have shown dopa-responsive dystonia (DRD) is 2.5-fold more common in women than men (PMID 3041760). Penetrance is shown to be reduced and ranges from 30 to 60% in men, but is higher in women (PMIDs: 9585358, 9566388).
Last Evaluated:
02/14/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 17898029
    This is a study of the frequency of point mutations and deletions of the gene GCH1 in patients with dopa-responsive dystonia (DRD). A total of 136 patients with dystonia were included. Sequencing was first performed and then qPCR analysis for patients in whom no point mutation had been detected. The patients were categorized based on clinical data and response to L-Dopa. Group 1 included patients with typical DRD symptoms (i.e. childhood onset of dystonia, circadian fluctuation) and a dramatic and sustained therapeutic response to L-Dopa without subsequent on-off phenomena (clinically definite DRD). Group 2 included patients with dystonia in whom clinical data was incomplete and/or the L-Dopa response was not striking or not tested. Fifty-four percent of patients in group 1 and 5% of patients in group 2 had point mutations. Mutations types included missense, nonsense, frame-shift and splice-site mutations. Entire gene deletions were detected in 4 patients. Testing of other family members was then offered to these patients. One family had four affected females over four generations. The affected female in the oldest generation did not have testing to confirm the presence of the deletion. Her unaffected son was confirmed to have the deletion. The son has two affected daughters, one confirmed to have the deletion. The daughter without confirmatory testing, has an affected daughter confirmed to have the deletion. Another family showed the affected female had a de novo gene deletion. Paternity was confirmed. A third family only had one affected family member that had a full deletion. No other family members were tested. The fourth family whose proband had gene deletion lacked confirmation of a definitive DRD diagnosis with limited attempt at L-Dopa intervention. This was the lone deletion categorized to group 2. Two other family members were reported to have symptoms but did not undergo genetic testing.
  • PUBMED: 19491146
    In this study, patients in whom dystonia improved by at least 50% after L-Dopa treatment were referred for molecular diagnosis. Sixty-four were tested with direct sequencing. Majority of patients were identified with heterozygous point mutations in GCH1, two with compound heterozygous mutations, and seven with heterozygous large deletions. Types of mutations identified included nonsense, missense, splice site, and mutation in the 5' untranslated region. MLPA was performed to detect deletions. Out of 64 patients, 7 had a deletion of or within the GCH1 gene. Two families had full gene deletions. One of these families had 4 individuals with complete gene deletion (2 males, 2 females). The index case presented with pure DRD, whereas the other patients had only mild equinism. Analysis of microsatellites and SNP in the region flanking the deletion demonstrated that the deletion encompassed only the GCH1 gene. The other family that had complete gene deletion had additional phenotypes and upon further testing was shown to have 2.3 Mb deletion containing 10 genes. Five of the seven families with deletions had partial deletion. Three patients with partial deletions (exons 2-6, 2-3, and 6, respectively) had no family history of affected family members. There is no information on if parental testing was performed in these families. One patient’s deletion included exon 1. In this family there was 1 female and 2 males affected but DNA was only available for genetic testing of the index patient (male). The family history of the other patient with a partial deletion of exons 4-6 included an affected mother and two daughters confirmed to have the partial deletion.
  • PUBMED: 17111153
    This article looks at three families with individuals affected with DRD and no sequence changes in GCH1. MLPA testing was performed to look for deletions. One family was found to have complete gene deletion in three members (a sister, a brother, and his child) all affected. Additionally, they report a family with 7 affected individuals with deletion of exons 4-6. A third family with 6 affected members were found to have deletion of exons 2-6. There was no discussion of the partial deletions resulting in lack of function.
HI Evidence Comments:
L-Dopa-responsive dystonia (DRD) is a childhood-onset disorder characterized by a dramatic response to low dose of L-Dopa. Typical presentation includes gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of systems. DRD can present in adult hood as focal dystonia or parkinsonism. Women are affected 2.5 -4 times more frequently than men, and symptoms can vary among affected individuals, even within a family. Sequence variants and deletions in GCH1 lead to DRD. Although the disorder has an autosomal dominant inheritance pattern, penetrance is reduced more in males than females. Missense, nonsense, splicing, intragenic small deletion/insertion, and gross deletion pathogenic variants have been reported. Complete gene deletions have been reported, supporting haploinsufficiency. Of note: this gene has also been evaluated by the ClinGen Aminoacidopathy GCEP. In their review, they note: "Biallelic variants in GCH1 typically result in severe deficiency of GTPCH activity, and result in hyperphenylalaninemia due to secondary PAH deficiency. This can be identified by newborn screening. However, patients with phenotypes that are intermediate between the classic DRD and severe GTPCH deficiency symptoms have been described, such those with severe DRD and additional neurological features but without hyperphenylalaninemia (for review, see Table in Brüggemann et al 2012, PMID 22473768)."

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000014.8) (NC_000014.9)