HGNC Approved Gene Symbol: UROD
SNOMEDCT: 111386004, 61860000; ICD10CM: E80.1;
Cytogenetic location: 1p34.1 Genomic coordinates (GRCh38) : 1:45,012,254-45,015,575 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.1 | Porphyria cutanea tarda | 176100 | Autosomal dominant; Autosomal recessive | 3 |
| Porphyria, hepatoerythropoietic | 176100 | Autosomal dominant; Autosomal recessive | 3 |
Uroporphyrinogen decarboxylase (UROD; EC 4.1.1.37) is a cytosolic enzyme involved in the biosynthesis of heme. It catalyzes the sequential removal of 4 of the carboxymethyl side chains of uroporphyrinogen to yield coproporphyrinogen. Sassa et al. (1983) purified UROD to homogeneity. A single enzyme is involved in the 4 successive decarboxylations.
Romeo et al. (1986) cloned and sequenced a full-length cDNA coding for human UROD. The deduced 367-amino acid protein has a molecular mass of 40.8 kD. Northern blot analysis demonstrated the presence of a single size species of mRNA in erythroid and nonerythroid tissues and in several cultured cell lines. The level of UROD mRNA was markedly increased in tissues and cell lines of erythroid origin.
Romana et al. (1987) demonstrated that the UROD gene has 10 exons spread over 3 kb.
De Verneuil et al. (1984) assigned the locus for uroporphyrinogen decarboxylase to chromosome 1 by somatic cell hybridization and specific enzyme assay. This was the fourth enzyme of the heme biosynthetic pathway to be mapped; the other 3 are CPOX (612732) on 9, PBGD (609806) on 11, and ALAD (125270) on 9. Mattei et al. (1985) used a cDNA clone to localize UROD to 1p34 by in situ hybridization. McLellan et al. (1985) arrived at a different location, 1pter-1p21, by somatic cell hybridization using cell lines with rearranged chromosomes. Using a cDNA probe in both somatic cell and in situ hybridization, Dubart et al. (1986) confirmed the assignment to 1p34.
Bahary et al. (1991) assigned the homologous Urod gene to chromosome 4 of the mouse.
Porphyria Cutanea Tarda
In the UROD cDNA from a patient with familial porphyria cutanea tarda (PCT; 176100), Garey et al. (1989) demonstrated a heterozygous gly281-to-val substitution (G281V; 613521.0001). The mutation was not detected in affected persons from 7 other PCT pedigrees with an autosomal dominant pattern of inheritance.
Hepatoerythropoietic Porphyria
In a Tunisian family with hepatoerythropoietic porphyria (HEP; see 176100), de Verneuil et al. (1988) identified homozygosity for a G281E mutation (613521.0002) in the UROD gene product.
In a patient with familial porphyria cutanea tarda (PCT; 176100), Garey et al. (1989) identified heterozygosity for a gly281-to-val (G281V) mutation in UROD cDNA.
De Verneuil et al. (1986) cloned and sequenced cDNA for the mutated gene in 1 of their 2 homozygous patients with hepatoerythropoietic porphyria (HEP; see 176100) and found that the glycine residue at position 281 was replaced by glutamic acid (G281E). This single amino acid change led to a protein that was rapidly degraded in the presence of cell lysate. Using a synthetic oligonucleotide probe to screen for the presence of the G281E mutation, de Verneuil et al. (1988) demonstrated the mutation in HEP-affected members of 2 unrelated families from Spain, but found that it was absent in 2 other HEP patients from Italy and Portugal. Moreover, the mutation was not detected in 13 unrelated cases of familial porphyria cutanea tarda.
Garey et al. (1989) demonstrated this substitution in homozygous state in a patient with HEP.
In a study of 5 Spanish families with hepatoerythropoietic porphyria and 9 unrelated Spanish patients with familial porphyria cutanea tarda, Roberts et al. (1995) found homozygosity for the G281E mutation in 4 patients with HEP and compound heterozygosity for this mutation in the fifth. The calculated carrier frequency for G281E in Spain was 1 in 1,800. None of the 9 familial porphyria cutanea tarda patients carried the G281E mutation. However, one G281E heterozygote in a family with hepatoerythropoietic porphyria had overt porphyria cutanea tarda (PCT; 176100). These findings suggested that the G281E mutation is functionally less severe than erythrocyte measurements indicate, that its clinical penetrance is very low in heterozygotes, and that, for this particular mutation, hepatoerythropoietic porphyria is the homozygous form of familial porphyria cutanea tarda. The results also indicated that HEP in Spain is genetically homogeneous, since 9 of the 10 UROD-deficient chromosomes carried the G281E mutation. In contrast, studies in most of the 14 families reported from outside Spain were likely to have different mutations. The parents of only 1 of the Spanish cases were consanguineous, and the other families came from widely different regions of Spain and did not appear to be related. The mutation probably entered Spain in the distant past and had become widely distributed. The G281E mutation was originally described in a Tunisian family (de Verneuil et al., 1988).
In a Spanish family, Moran-Jimenez et al. (1996) found homozygosity for the G281E mutation as the cause of HEP. A paternal uncle of the proband developed clinically overt porphyria cutanea tarda as an adult and proved to be heterozygous for the G281E mutation.
In affected members of 5 of 22 unrelated families segregating porphyria cutanea tarda (PCT; 176100), Garey et al. (1990) found a heterozygous splice site mutation in the UROD gene (IVS6+1G-C). The mutation resulted in the deletion of exon 6. The intron/exon junctions on either side of exon 6 fall between codons; thus, the resulting protein is shorter than the normal protein, missing only the amino acids coded by exon 6. The shortened protein lacked catalytic activity, was rapidly degraded when exposed to human lymphocyte lysates, and was not detectable by Western blot analysis in lymphocyte lysates derived from affected persons.
Romana et al. (1991) demonstrated that a patient with hepatoerythropoietic porphyria (HEP; see 176100) was homozygous for a GAG-to-AAG mutation in the UROD gene that changed glutamic acid-167 to lysine (E167K).
In 2 Dutch sisters with hepatoerythropoietic porphyria (HEP; see 176100), de Verneuil et al. (1992) demonstrated compound heterozygosity for a deletion inherited from the father and an R292G mutation inherited from the mother.
In affected members of a Portuguese family segregating hepatoerythropoietic porphyria (HEP; see 176100), Moran-Jimenez et al. (1996) demonstrated homozygosity for a pro61-to-leu (P62L) substitution in UROD. Mutant cDNA corresponding to the P62L change was created by site-directed mutagenesis. The recombinant protein proved to have subnormal enzyme activity.
In an Italian family, Moran-Jimenez et al. (1996) identified a tyr311-to-cys (Y311C) substitution in homoallelic state in the UROD gene as the cause of hepatoerythropoietic porphyria (HEP; see 176100). Mutant cDNA corresponding to the Y311C change was created by site-directed mutagenesis. The recombinant protein proved to have subnormal enzyme activity and was thermolabile.
In their family 1 with porphyria cutanea tarda (PCT; 176100), Mendez et al. (1998) found that the proband had a heterozygous G-to-A transition in the last base of exon 9 of the UROD gene causing a GAG (glu) to GAA (glu) change at codon 314; the amino acid sequence was not altered. However, the splicing of intron 9 was defective; the entire 67-bp exon 9 was deleted and exon 8 was joined directly to exon 10.
In a patient of Italian ancestry with porphyria cutanea tarda (PCT; 176100), Mendez et al. (1998) identified a heterozygous met165-to-arg substitution in the UROD gene product.
In a patient of Spanish ancestry with porphyria cutanea tarda (PCT; 176100), Mendez et al. (1998) identified a heterozygous leu195-to-phe (L195F) substitution in the UROD gene product.
In a patient of Spanish ancestry with porphyria cutanea tarda (PCT; 176100), Mendez et al. (1998) identified a heterozygous asn304-to-lys (N304K) substitution in the UROD gene product.
In a patient of Portuguese ancestry with porphyria cutanea tarda (PCT; 176100), Mendez et al. (1998) identified a heterozygous arg332-to-his (R332H) substitution in the UROD gene product.
In a Spanish patient with porphyria cutanea tarda (PCT; 176100), Badenas et al. (2009) identified a 10-bp deletion in exon 1 of the UROD gene (5del10).
In a Spanish patient with porphyria cutanea tarda (PCT; 176100), Badenas et al. (2009) identified a 346C-T transition in exon 5 of the UROD gene, resulting in a gln116-to-ter (Q116X) substitution.
Badenas, C., To-Figueras, J., Phillips, J. D., Warby, C. A., Munoz, C., Herrero, C. Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Clin. Genet. 75: 346-353, 2009. [PubMed: 19419417] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01153.x]
Bahary, N., Zorich, G., Pachter, J. E., Leibel, R. L., Friedman, J. M. Molecular genetic linkage maps of mouse chromosomes 4 and 6. Genomics 11: 33-47, 1991. [PubMed: 1684952] [Full Text: https://doi.org/10.1016/0888-7543(91)90099-z]
de Verneuil, H., Bourgeois, F., de Rooij, F., Siersema, P. D., Wilson, J. H. P., Grandchamp, B., Nordmann, Y. Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria. Hum. Genet. 89: 548-552, 1992. [PubMed: 1634232] [Full Text: https://doi.org/10.1007/BF00219182]
de Verneuil, H., Grandchamp, B., Beaumont, C., Picat, C., Nordmann, Y. Uroporphyrinogen decarboxylase structural mutant (gly281-to-glu) in a case of porphyria. Science 234: 732-734, 1986. [PubMed: 3775362] [Full Text: https://doi.org/10.1126/science.3775362]
de Verneuil, H., Grandchamp, B., Foubert, C., Weil, D., Van Cong, N., Gross, M.-S., Sassa, S., Nordmann, Y. Assignment of the gene for uroporphyrinogen decarboxylase to human chromosome 1 by somatic cell hybridization and specific enzyme immunoassay. Hum. Genet. 66: 202-205, 1984. [PubMed: 6370830] [Full Text: https://doi.org/10.1007/BF00286601]
de Verneuil, H., Grandchamp, B., Romeo, P. H., Raich, N., Beaumont, C., Goossens, M., Nicolas, H., Nordmann, Y. Molecular analysis of uroporphyrinogen decarboxylase deficiency in a family with two cases of hepatoerythropoietic porphyria. J. Clin. Invest. 77: 431-435, 1986. [PubMed: 3753711] [Full Text: https://doi.org/10.1172/JCI112321]
de Verneuil, H., Hansen, J., Picat, C., Grandchamp, B., Kushner, J., Roberts, A., Elder, G., Nordmann, Y. Prevalence of the 281 (gly-to-glu) mutation in hepatoerythropoietic porphyria and porphyria cutanea tarda. Hum. Genet. 78: 101-102, 1988. [PubMed: 2892774] [Full Text: https://doi.org/10.1007/BF00291248]
Dubart, A., Mattei, M. G., Raich, N., Beaupain, D., Romeo, P. H., Mattei, J. F., Goossens, M. Assignment of human uroporphyrinogen decarboxylase (URO-D) to the p34 band of chromosome 1. Hum. Genet. 73: 277-279, 1986. [PubMed: 3460962] [Full Text: https://doi.org/10.1007/BF00401245]
Garey, J. R., Hansen, J. L., Harrison, L. M., Kennedy, J. B., Kushner, J. P. A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda. Blood 73: 892-895, 1989. [PubMed: 2920211]
Garey, J. R., Hansen, J. L., Kushner, J. P. The molecular basis of familial porphyria cutanea tarda (F-PCT). (Abstract) Clin. Res. 36: 612A, 1988.
Garey, J. R., Harrison, L. M., Franklin, K. F., Metcalf, K. M., Radisky, E. S., Kushner, J. P. Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda. J. Clin. Invest. 86: 1416-1422, 1990. [PubMed: 2243121] [Full Text: https://doi.org/10.1172/JCI114856]
Mattei, M. G., Dubart, A., Beaupain, D., Goossens, M., Mattei, J. F. Localization of the uroporphyrinogen decarboxylase gene to 1p34 band, by in situ hybridization. (Abstract) Cytogenet. Cell Genet. 40: 692, 1985.
McLellan, T., Pryor, M. A., Kushner, J. P., Eddy, R. L., Shows, T. B. Assignment of uroporphyrinogen decarboxylase (UROD) to the pter-p21 region of human chromosome 1. Cytogenet. Cell Genet. 39: 224-227, 1985. [PubMed: 4042691] [Full Text: https://doi.org/10.1159/000132139]
Mendez, M., Sorkin, L., Rossetti, M. V., Astrin, K. H., Batlle, A. M. del C., Parera, V. E., Aizencang, G., Desnick, R. J. Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am. J. Hum. Genet. 63: 1363-1375, 1998. [PubMed: 9792863] [Full Text: https://doi.org/10.1086/302119]
Moran-Jimenez, M. J., Ged, C., Romana, M., Enriquez de Salamanca, R., Taieb, A., Topi, G., D'Alessandro, L., de Verneuil, H. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am. J. Hum. Genet. 58: 712-721, 1996. [PubMed: 8644733]
Roberts, A. G., Elder, G. H., De Salamanca, R. E., Herrero, C., Lecha, M., Mascaro, J. M. A mutation (G281E) of the human uroporphyrinogen decarboxylase gene causes both hepatoerythropoietic porphyria and overt familial porphyria cutanea tarda: biochemical and genetic studies on Spanish patients. J. Invest. Derm. 104: 500-502, 1995. [PubMed: 7706766] [Full Text: https://doi.org/10.1111/1523-1747.ep12605953]
Romana, M., Dubart, A., Beaupain, D., Chabret, C., Goossens, M., Romeo, P.-H. Structure of the gene for human uroporphyrinogen decarboxylase. Nucleic Acids Res. 15: 7343-7356, 1987. [PubMed: 3658695] [Full Text: https://doi.org/10.1093/nar/15.18.7343]
Romana, M., Grandchamp, B., Dubart, A., Amselem, S., Chabret, C., Nordmann, Y., Goossens, M., Romeo, P.-H. Identification of a new mutation responsible for hepatoerythropoietic porphyria. Europ. J. Clin. Invest. 21: 225-229, 1991. [PubMed: 1905636] [Full Text: https://doi.org/10.1111/j.1365-2362.1991.tb01814.x]
Romeo, P.-H., Raich, N., Dubart, A., Beaupain, D., Pryor, M., Kushner, J., Cohen-Solal, M., Goossens, M. Molecular cloning and nucleotide sequence of a complete human uroporphyrinogen decarboxylase cDNA. J. Biol. Chem. 261: 9825-9831, 1986. [PubMed: 3015909]
Sassa, S., de Verneuil, H., Anderson, K. E., Kappas, A. Purification and properties of human erythrocyte uroporphyrinogen decarboxylase: immunological demonstration of the enzyme defect in porphyria cutanea tarda. Trans. Assoc. Am. Phys. 96: 65-75, 1983. [PubMed: 6437037]