PCBD1
protein-codingpterin-4 alpha-carbinolamine dehydratase 1
Gene summary
This gene encodes a member of the pterin-4-alpha-carbinolamine dehydratase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The encoded protein functions as both a dehydratase involved in tetrahydrobiopterin biosynthesis, and as a cofactor for HNF1A-dependent transcription. A deficiency of this enzyme leads to hyperphenylalaninemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
- DCOH
- PCBD
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009908
Submitter: ClinGen
PCBD1 was first reported in relation to autosomal recessive pterin-4 alpha-carbinolamine dehydratase (PCD) deficiency by Thony et al in 1998 (PMID: 9585615). PCD deficiency is a transient form of hyperphenylalaninemia caused by a deficiency in tetrahydrobiopterin (BH4) (reviewed in PMIDs: 19234759, 22729819, 16917893). BH4 is an essential cofactor for the phenylalanine, tyrosine, and tryptophan hydroxylates, thus variation in genes associated with this metabolic pathway can result in the development of hyperphenylalaninemia (reviewed in PMIDs: 19234759, 22729819, 16917893). Evidence supporting this gene-disease relationship includes case-level data, functional data, and model organisms. Hyperphenylalaninemia disorders are heterogeneous and have been linked to neurological abnormalities, however PCBD1 appears to be linked to a more benign form of the disease (PMID: 16917893). Approximately 5% of BH4 deficiency is accounted to this variation in PCBD1 (reviewed in PMID: 19234759). BIODEF, a database of patient and variant information for some metabolic disorders, contains data for at least 30 individuals with variation in this gene (http://www.biopku.org/biodef/BIODEF_Start.asp). The majority of these individuals were noted as having transient hyperphenylalaninemia, with few noted to have a mild peripheral phenotype. The mechanism for this gene-disease relationship is perturbation of BH4 regeneration, which may lead to excessive phenylalanine and primapterin levels in blood, urine, and tissues (reviewed in PMID: 19234759). One report has asserted a role of PCBD1 in maturity onset diabetes of the young (MODY) (Simaite et al., 2014 PMID: 24848070), based on evidence to suggest that PCBD1 binds to and acts as a cofactor for HNF1A, a gene that is implicated in MODY, and linkage data in the family at the PCBD1 locus. Review of the segregation evidence among the families reported showed non-segregation of the PCBD1 variation, meaning individuals were positive for a MODY (or an unspecified form of diabetes) and negative for the PCBD1 mutation. Furthermore, several of the implicated individuals had a diabetes phenotype and had autosomal dominant inheritance of the PCBD1, which is inconsistent with PCD deficiency’s recessive inheritance pattern. While the preliminary evidence is compelling, at this time there is insufficient evidence to link the phenotype of MODY with PCD deficiency, therefore these individuals were not included as part of the gene-disease curation at this time. In summary, PCBD1 is definitively associated with autosomal recessive pterin-4 alpha-carbinolamine dehydratase (PCD). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy GCEP on February 22, 2019 (SOP Version 6).
Inheritance Pattern: AR
Disease ID:MONDO:0009908
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009908
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009908
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009908
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009908
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009908
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Endocrine; Renal
Intervention: Renal
Rationale: In addition to other findings, patients may develop hypomagnesemia with renal magnesium loss, and awareness may allow medical management (magnesium supplementation), which has been reported as clinically beneficial
Comments: Individuals have been treated with phenylalanine restriction and BH4 supplementation, but such interventions may not be indicated
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PCBD1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000281.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 34 | 34 | ||||
| missense | 2 | 20 | 1 | 23 | ||
| nonsense | 3 | 1 | 4 | |||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 4 | 9 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 5 | 12 | 21 | 35 | 0 | 73 |
Highest pathogenic variant AF is 0.00019701773
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000272.1 | 4 | MANE Select | |
| Ensembl | ENSP00000299299.3 | 4 | MANE Select | |
| RefSeq | NP_001276726.1 | 2 | Standard | |
| RefSeq | NP_001309933.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Folate biosynthesis - Homo sapiens (human)
- phenylalanine degradation/tyrosine biosynthesis
- Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism
- Metabolism of amino acids and derivatives
- Phenylalanine and tyrosine catabolism
Biological Process
- L-phenylalanine catabolic process
- tetrahydrobiopterin biosynthetic process
- regulation of protein homodimerization activity
- positive regulation of transcription, DNA-templated
- protein homotetramerization
Molecular Function
- transcription coactivator activity
- phenylalanine 4-monooxygenase activity
- protein binding
- 4-alpha-hydroxytetrahydrobiopterin dehydratase activity
- identical protein binding
Cellular Component
- nucleus
- nucleoplasm
- cytosol
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000299299
- Coding exons
- 4
- Length
- 6505
- Individuals with no LoFs
- 125723
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 125748
- p
- 0.0000994
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.716 | 42 | 57.2 | 0.734 | 0.00000338 | 693 |
| Missense (PolyPhen) | 16 | 22.696 | 0.70497 | 265 | ||
| Synonymous | -0.486 | 27 | 24.0 | 1.13 | 0.00000150 | 189 |
| Loss of Function | -0.107 | 5 | 4.75 | 1.05 | 2.07e-7 | 62 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.0013 | 0.0013 | notable |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in tetrahydrobiopterin biosynthesis. Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2. Coactivator for HNF1A-dependent transcription. Regulates the dimerization of homeodomain protein HNF1A and enhances its transcriptional activity.;
- Disease
- DISEASE: Hyperphenylalaninemia, BH4-deficient, D (HPABH4D) [MIM:264070]: An autosomal recessive disease characterized by primapterinuria, a variant form of hyperphenylalaninemia defined by increased excretion of 7-substituted pterins in the urine. Patients with primapterinuria show an increased ratio of neopterin to biopterin in the urine, excretion of subnormal levels of biopterins, and normal levels of biogenic amines in cerebrospinal fluid. Neurologic signs are mild, present in the neonatal period only, and include hypotonia, delayed motor development and tremor. {ECO:0000269|PubMed:8352282, ECO:0000269|PubMed:9760199}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.230
Intolerance Scores
- LoFtool
- 0.574
- RVIS EVS
- 0.01
- RVIS percentile EVS
- 54.63
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.973
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |