UROD
protein-codinguroporphyrinogen decarboxylase
Gene summary
This gene encodes an enzyme in the heme biosynthetic pathway. This enzyme is responsible for catalyzing the conversion of uroporphyrinogen to coproporphyrinogen through the removal of four carboxymethyl side chains. Mutations and deficiency in this enzyme are known to cause familial porphyria cutanea tarda and hepatoerythropoetic porphyria.[provided by RefSeq, Aug 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: SD
Disease ID:MONDO:0100498
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008296
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0100498
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008296
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008296
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008296
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019799
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008296
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0100498
Submitter: ClinGen
The *UROD* gene was first reported in relation to inherited porphyria with the 1986 publication of an affected patient harboring a variant in the homozygous state (PMID: 3775362). Affected individuals harboring biallelic variants are typically diagnosed with hepatoerythropoietic porphyria, and generally present in infancy or childhood with cutaneous photosensitivity, blistering and hyperpigmentation of sun-exposed skin, severe uroporphyrinuria, erythrocyte deficiency of UROD enzymatic activity, and sometimes liver damage. Inherited porphyria has been reported in association with *UROD* variants in the heterozygous state as well, starting with the 1989 publication of a patient with familial porphyria cutanea tarda (PMID: 2920211). Cases with this diagnosis generally exhibit similar but less severe presentation, incomplete penetrance, and adult onset induced by triggers such as iron overload, use of alcohol or estrogens, or viral infections such as hepatitis C. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (UROD loss-of-function) has been found to be consistent between the hepatoerythropoietic porphyria cases with biallelic variants and the familial porphyria cutanea tarda cases with monoallelic variants. In addition, the phenotypic differences between the biallelic and monoallelic cases appear to represent a single spectrum of disease. Therefore, cases caused by inherited *UROD* variants have been lumped into a single disease entity referred to as *UROD*-related inherited porphyria (MONDO:0100498, MIM #176100), with a semidominant mode of inheritance. Eleven suspected pathogenic variants have been scored as part of this curation (six missense, two nonsense, one frameshift, one disrupting the start codon, and one triggering splicing defects), which have been collectively reported in eleven probands in six publications (PMID: 2243121, PMID: 2920211, PMID: 3775362, PMID: 8644733, PMID: 19419417, PMID: 34367815). The mechanism of pathogenicity appears to be monoallelic or biallelic loss of UROD function conferred by null and/or hypomorphic variants. Monoallelic cases have approximately 50% of normal UROD enzymatic function at the cellular level (PMID: 7062951) but exhibit less than 10% penetrance due to the requirement for a trigger to further depress UROD enzymatic levels to approximately 20% of normal. Iron overload appears act as a trigger by inhibiting cytochrome P450 enzymes, resulting in the production of reactive oxygen species that react with the uroporphyrinogen substrates to generate UROD inhibitors (PMID: 9763408). Biallelic cases appear to retain between 5% and 14% of normal UROD enzymatic function, depending on the tissue examined (PMID: 8644733). Nine out of eleven probands included in this curation were heterozygous for their respective variants, while two probands were homozygous. Segregation evidence was available in one of these publications (PMID: 2243121) and has contributed to the scoring of the gene-disease relationship. Additional case-level evidence is available in the literature but has not been included in this curation as the maximum score for this category of evidence has already been reached. This gene-disease association is also supported experimental evidence demonstrating that *UROD* encodes the human enzyme responsible for catalyzing coproporphyrinogen III synthesis from uroporphyrinogen III (PMID: 6370830). This represents a critical step in the heme biosynthesis pathway and is consistent with the very high levels of uroporphyrin and heptacarboxylporphyrin in the urine of affected patients. Genetically engineered mouse and naturally occurring zebrafish models have shown that either monoallelic (PMID: 11134514) or biallelic (PMID: 9806541) *UROD* loss-of-function can recapitulate many of the molecular and systemic phenotypes observed in human patients, including urinary accumulation of uroporphyrin and heptacarboxylporphyrin, hepatic accumulation of iron, photosensitivity, and hematological defects, which in some cases can be rescued by expression of a wild-type transgene (PMID: 9806541). In summary, *UROD* is definitively associated with *UROD*-related inherited porphyria. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on August 12th, 2022 (SOP Version 9).
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Dermatologic; Gastrointestinal; Hematologic
Intervention: Dermatologic; Hematologic; Pharmacogenomic
Rationale: Treatment involves management of iron overload (eg, by phlebotomy); Exacerbating factors (eg, iron overload, excessive alcohol use, polyhalogenated aromatic chemicals, estrogens, etc.) should be avoided; Skin protection is warranted
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to UROD variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000374.5. 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 | 1 | 3 | 9 | 13 | ||
| missense | 8 | 16 | 77 | 7 | 108 | |
| nonsense | 10 | 4 | 14 | |||
| start loss | 1 | 1 | ||||
| frameshift | 10 | 6 | 1 | 17 | ||
| splice donor/acceptor (+/-2bp) | 4 | 6 | 8 | 18 | ||
| Total | 33 | 33 | 89 | 16 | 0 | 171 |
Highest pathogenic variant AF is 0.00011832809
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000365.3 | 10 | MANE Select | |
| Ensembl | ENSP00000246337.4 | 10 | MANE Select | |
| Ensembl | ENSP00000400253.1 | 6 | Standard | |
| Ensembl | ENSP00000404489.2 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| urod | Danio rerio | Structure: nucleate erythrocyte Quality: increased fluorescence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Porphyrin and chlorophyll metabolism - Homo sapiens (human)
- Hereditary Coproporphyria (HCP)
- Porphyria Variegata (PV)
- Congenital Erythropoietic Porphyria (CEP) or Gunther Disease
- Acute Intermittent Porphyria
Biological Process
- protoporphyrinogen IX biosynthetic process
- heme biosynthetic process
Molecular Function
- uroporphyrinogen decarboxylase activity
- protein binding
Cellular Component
- nucleoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000246337
- Coding exons
- 10
- Length
- 3429
- Individuals with no LoFs
- 125692
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 56
- Defined
- 125748
- p
- 0.000223
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.11 | 165 | 210 | 0.784 | 0.0000122 | 2358 |
| Missense (PolyPhen) | 63 | 99.591 | 0.63259 | 1151 | ||
| Synonymous | 0.734 | 70 | 78.3 | 0.894 | 0.00000388 | 767 |
| Loss of Function | 1.13 | 15 | 20.5 | 0.731 | 0.00000109 | 226 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00061 | 0.00061 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00018 | 0.00018 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the decarboxylation of four acetate groups of uroporphyrinogen-III to yield coproporphyrinogen-III.;
- Disease
- DISEASE: Familial porphyria cutanea tarda (FPCT) [MIM:176100]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Familial porphyria cutanea tarda is an autosomal dominant disorder characterized by light-sensitive dermatitis, with onset in later life. It is associated with the excretion of large amounts of uroporphyrin in the urine. Iron overload is often present in association with varying degrees of liver damage. {ECO:0000269|PubMed:10338097, ECO:0000269|PubMed:10477430, ECO:0000269|PubMed:11069625, ECO:0000269|PubMed:11295834, ECO:0000269|PubMed:11719352, ECO:0000269|PubMed:2243121, ECO:0000269|PubMed:2920211, ECO:0000269|PubMed:7706766, ECO:0000269|PubMed:8896428, ECO:0000269|PubMed:9792863}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hepatoerythropoietic porphyria (HEP) [MIM:176100]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. HEP is a cutaneous porphyria that presents in infancy. It is characterized biochemically by excessive excretion of acetate-substituted porphyrins and accumulation of protoporphyrin in erythrocytes. Uroporphyrinogen decarboxylase levels are very low in erythrocytes and cultured skin fibroblasts. {ECO:0000269|PubMed:12071824, ECO:0000269|PubMed:15491440, ECO:0000269|PubMed:1634232, ECO:0000269|PubMed:17240319, ECO:0000269|PubMed:1905636, ECO:0000269|PubMed:21668429, ECO:0000269|PubMed:3775362, ECO:0000269|PubMed:8176248, ECO:0000269|PubMed:8644733, ECO:0000269|PubMed:8896428}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.229
Intolerance Scores
- LoFtool
- 0.180
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.73
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |