| Structural highlights
Disease
HEM4_HUMAN Defects in UROS are the cause of congenital erythropoietic porphyria (CEP) [MIM:263700; also known as Gunther disease. 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. The manifestations of CEP are heterogeneous, ranging from nonimmune hydrops fetalis due to severe hemolytic anemia in utero to milder, later onset forms, which have only skin lesions due to cutaneous photosensitivity in adult life. The deficiency in UROS activity results in the non-enzymatic conversion of hydroxymethylbilane (HMB) into the uroporphyrinogen-I isomer.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Note=Severe congenital erythropoietic porphyria is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders.
Function
HEM4_HUMAN Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins. Porphyrins act as cofactors for a multitude of enzymes that perform a variety of processes within the cell such as methionine synthesis (vitamin B12) or oxygen transport (heme).Q9YBB1_AERPE
References
- ↑ Deybach JC, de Verneuil H, Boulechfar S, Grandchamp B, Nordmann Y. Point mutations in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria (Gunther's disease). Blood. 1990 May 1;75(9):1763-5. PMID:2331520
- ↑ Boulechfar S, Da Silva V, Deybach JC, Nordmann Y, Grandchamp B, de Verneuil H. Heterogeneity of mutations in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria. Hum Genet. 1992 Jan;88(3):320-4. PMID:1733834
- ↑ Warner CA, Yoo HW, Roberts AG, Desnick RJ. Congenital erythropoietic porphyria: identification and expression of exonic mutations in the uroporphyrinogen III synthase gene. J Clin Invest. 1992 Feb;89(2):693-700. PMID:1737856 doi:https://dx.doi.org/10.1172/JCI115637
- ↑ Xu W, Warner CA, Desnick RJ. Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene. J Clin Invest. 1995 Feb;95(2):905-12. PMID:7860775 doi:https://dx.doi.org/10.1172/JCI117742
- ↑ Tanigawa K, Bensidhoum M, Takamura N, Namba H, Yamashita S, de Verneuil H, Ged C. A novel point mutation in congenital erythropoietic porphyria in two members of Japanese family. Hum Genet. 1996 May;97(5):557-60. PMID:8655129
- ↑ Takamura N, Hombrados I, Tanigawa K, Namba H, Nagayama Y, de Verneuil H, Yamashita S. Novel point mutation in the uroporphyrinogen III synthase gene causes congenital erythropoietic porphyria of a Japanese family. Am J Med Genet. 1997 Jun 13;70(3):299-302. PMID:9188670
- ↑ Tezcan I, Xu W, Gurgey A, Tuncer M, Cetin M, Oner C, Yetgin S, Ersoy F, Aizencang G, Astrin KH, Desnick RJ. Congenital erythropoietic porphyria successfully treated by allogeneic bone marrow transplantation. Blood. 1998 Dec 1;92(11):4053-8. PMID:9834209
- ↑ Frank J, Wang X, Lam HM, Aita VM, Jugert FK, Goerz G, Merk HF, Poh-Fitzpatrick MB, Christiano AM. C73R is a hotspot mutation in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria. Ann Hum Genet. 1998 May;62(Pt 3):225-30. PMID:9803266 doi:10.1046/j.1469-1809.1998.6230225.x
- ↑ Rogounovitch T, Takamura N, Hombrados I, Morel C, Tanaka T, Kameyoshi Y, Shimizu-Yoshida Y, de Verneuil H, Yamashita S. Congenital erythropoietic porphyria: a novel homozygous mutation in a Japanese patient. J Invest Dermatol. 2000 Dec;115(6):1156. PMID:11121156 doi:10.1046/j.1523-1747.2000.0202a.x
- ↑ Shady AA, Colby BR, Cunha LF, Astrin KH, Bishop DF, Desnick RJ. Congenital erythropoietic porphyria: identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene. Br J Haematol. 2002 Jun;117(4):980-7. PMID:12060141
- ↑ Ged C, Megarbane H, Chouery E, Lalanne M, Megarbane A, de Verneuil H. Congenital erythropoietic porphyria: report of a novel mutation with absence of clinical manifestations in a homozygous mutant sibling. J Invest Dermatol. 2004 Sep;123(3):589-91. PMID:15304101 doi:10.1111/j.0022-202X.2004.23401.x
- ↑ To-Figueras J, Ducamp S, Clayton J, Badenas C, Delaby C, Ged C, Lyoumi S, Gouya L, de Verneuil H, Beaumont C, Ferreira GC, Deybach JC, Herrero C, Puy H. ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria. Blood. 2011 Aug 11;118(6):1443-51. doi: 10.1182/blood-2011-03-342873. Epub 2011, Jun 7. PMID:21653323 doi:10.1182/blood-2011-03-342873
- ↑ Moghbeli M, Maleknejad M, Arabi A, Abbaszadegan MR. Mutational analysis of uroporphyrinogen III cosynthase gene in Iranian families with congenital erythropoietic porphyria. Mol Biol Rep. 2012 Jun;39(6):6731-5. doi: 10.1007/s11033-012-1497-z. Epub 2012, Feb 18. PMID:22350154 doi:10.1007/s11033-012-1497-z
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