| Structural highlights
Disease
[DCUP_HUMAN] Defects in UROD are the cause of familial porphyria cutanea tarda (FPCT) [MIM:176100]; also known as porphyria cutanea tarda type II. FPCT 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. Besides the familial form of PCT, a relatively common idiosyncratic form is known in which only the liver enzyme is reduced. This form is referred to as porphyria cutanea tarda "sporadic" type or type I [MIM:176090]. PCT type I occurs sporadically as an unusual accompaniment of common hepatic disorders such as alcohol-associated liver disease.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in UROD are the cause of hepatoerythropoietic porphyria (HEP) [MIM:176100]. HEP is a rare autosomal recessive disorder. It is the severe form of cutaneous porphyria, and presents in infancy. The level of UROD is very low in erythrocytes and cultured skin fibroblasts, suggesting that HEP is the homozygous state for porphyria cutanea tarda.[11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
Function
[DCUP_HUMAN] Catalyzes the decarboxylation of four acetate groups of uroporphyrinogen-III to yield coproporphyrinogen-III.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria in humans. The disorder is caused by homozygosity or compound heterozygosity for mutations of the uroporphyrinogen decarboxylase (URO-D) gene. Subnormal URO-D activity results in accumulation of uroporphyrin in the liver, which ultimately mediates the photosensitivity that clinically characterizes HEP. Two previously undescribed URO-D mutations found in a 2-year-old Caucasian boy with HEP, a maternal nonsense mutation (Gln71Stop), and a paternal missense mutation (Gly168Arg) are reported here. Recombinant Gly168Arg URO-D retained 65% of wild-type URO-D activity and studies in Epstein-Barr Virus (EBV)-transformed lymphoblasts indicated that protein levels are reduced, suggesting that the mutant protein might be subjected to accelerated turnover. The crystal structure of Gly168Arg was determined both as the apo-enzyme and with the reaction product bound. These studies revealed little distortion of the active site, but a loop containing residues 167-172 was displaced, possibly indicating small changes in the catalytic geometry or in substrate binding or increased accessibility to a cellular proteolytic pathway. A second pregnancy occurred in this family, and in utero genotyping revealed a fetus heterozygous for the maternal nonsense mutation (URO-D genotype WT/Gln71Stop). A healthy infant was born with no clinical evidence of porphyria.
Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP).,Phillips JD, Whitby FG, Stadtmueller BM, Edwards CQ, Hill CP, Kushner JP Transl Res. 2007 Feb;149(2):85-91. PMID:17240319[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Garey JR, Harrison LM, Franklin KF, Metcalf KM, Radisky ES, Kushner JP. Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda. J Clin Invest. 1990 Nov;86(5):1416-22. PMID:2243121 doi:http://dx.doi.org/10.1172/JCI114856
- ↑ Phillips JD, Parker TL, Schubert HL, Whitby FG, Hill CP, Kushner JP. Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase. Blood. 2001 Dec 1;98(12):3179-85. PMID:11719352
- ↑ Garey JR, Hansen JL, Harrison LM, Kennedy JB, Kushner JP. A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda. Blood. 1989 Mar;73(4):892-5. PMID:2920211
- ↑ Roberts AG, Elder GH, De Salamanca RE, Herrero C, Lecha M, Mascaro JM. 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 Dermatol. 1995 Apr;104(4):500-2. PMID:7706766
- ↑ McManus JF, Begley CG, Sassa S, Ratnaike S. Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria. Blood. 1996 Nov 1;88(9):3589-600. PMID:8896428
- ↑ Mendez M, Sorkin L, Rossetti MV, Astrin KH, del C Batlle AM, Parera VE, Aizencang G, Desnick RJ. Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am J Hum Genet. 1998 Nov;63(5):1363-75. PMID:9792863
- ↑ McManus JF, Begley CG, Sassa S, Ratnaike S. Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. Mutation in brief no. 237. Online. Hum Mutat. 1999;13(5):412. PMID:10338097 doi:<412::AID-HUMU11>3.0.CO;2-T 10.1002/(SICI)1098-1004(1999)13:5<412::AID-HUMU11>3.0.CO;2-T
- ↑ Christiansen L, Ged C, Hombrados I, Brons-Poulsen J, Fontanellas A, de Verneuil H, Horder M, Petersen NE. Screening for mutations in the uroporphyrinogen decarboxylase gene using denaturing gradient gel electrophoresis. Identification and characterization of six novel mutations associated with familial PCT. Hum Mutat. 1999;14(3):222-32. PMID:10477430 doi:<222::AID-HUMU5>3.0.CO;2-V 10.1002/(SICI)1098-1004(1999)14:3<222::AID-HUMU5>3.0.CO;2-V
- ↑ Brady JJ, Jackson HA, Roberts AG, Morgan RR, Whatley SD, Rowlands GL, Darby C, Shudell E, Watson R, Paiker J, Worwood MW, Elder GH. Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda. J Invest Dermatol. 2000 Nov;115(5):868-74. PMID:11069625 doi:jid148
- ↑ Cappellini MD, Martinez di Montemuros F, Tavazzi D, Fargion S, Pizzuti A, Comino A, Cainelli T, Fiorelli G. Seven novel point mutations in the uroporphyrinogen decarboxylase (UROD) gene in patients with familial porphyria cutanea tarda (f-PCT). Hum Mutat. 2001 Apr;17(4):350. PMID:11295834 doi:10.1002/humu.35
- ↑ McManus JF, Begley CG, Sassa S, Ratnaike S. Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria. Blood. 1996 Nov 1;88(9):3589-600. PMID:8896428
- ↑ Moran-Jimenez MJ, 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. 1996 Apr;58(4):712-21. PMID:8644733
- ↑ de Verneuil H, Grandchamp B, Beaumont C, Picat C, Nordmann Y. Uroporphyrinogen decarboxylase structural mutant (Gly281----Glu) in a case of porphyria. Science. 1986 Nov 7;234(4777):732-4. PMID:3775362
- ↑ Romana M, Grandchamp B, Dubart A, Amselem S, Chabret C, Nordmann Y, Goossens M, Romeo PH. Identification of a new mutation responsible for hepatoerythropoietic porphyria. Eur J Clin Invest. 1991 Apr;21(2):225-9. PMID:1905636
- ↑ de Verneuil H, Bourgeois F, de Rooij F, Siersema PD, Wilson JH, 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. 1992 Jul;89(5):548-52. PMID:1634232
- ↑ Meguro K, Fujita H, Ishida N, Akagi R, Kurihara T, Galbraith RA, Kappas A, Zabriskie JB, Toback AC, Harber LC, et al.. Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria. J Invest Dermatol. 1994 May;102(5):681-5. PMID:8176248
- ↑ Ged C, Ozalla D, Herrero C, Lecha M, Mendez M, de Verneuil H, Mascaro JM. Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus. Arch Dermatol. 2002 Jul;138(7):957-60. PMID:12071824
- ↑ Armstrong DK, Sharpe PC, Chambers CR, Whatley SD, Roberts AG, Elder GH. Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol. 2004 Oct;151(4):920-3. PMID:15491440 doi:BJD6101
- ↑ Phillips JD, Whitby FG, Stadtmueller BM, Edwards CQ, Hill CP, Kushner JP. Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Transl Res. 2007 Feb;149(2):85-91. PMID:17240319 doi:10.1016/j.trsl.2006.08.006
- ↑ To-Figueras J, Phillips JD, Gonzalez-Lopez JM, Badenas C, Madrigal I, Gonzalez-Romaris EM, Ramos C, Aguirre JM, Herrero C. Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. Br J Dermatol. 2011 Sep;165(3):499-505. doi: 10.1111/j.1365-2133.2011.10453.x., Epub 2011 Aug 18. PMID:21668429 doi:10.1111/j.1365-2133.2011.10453.x
- ↑ Phillips JD, Whitby FG, Stadtmueller BM, Edwards CQ, Hill CP, Kushner JP. Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Transl Res. 2007 Feb;149(2):85-91. PMID:17240319 doi:10.1016/j.trsl.2006.08.006
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