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Pathway Description
Congenital Erythropoietic Porphyria (CEP) or Gunther Disease
Homo sapiens
Disease Pathway
Created: 2013-08-19
Last Updated: 2022-11-10
Congenital Erythropoietic Porphyria (CEP), also known as Gunther Disease, uroporphyrinogen III synthase defiency or UROS deficiency, is a rare autosomal recessive rare inborn error of metabolism (IEM). It is a disorder of the porphyrin metabolism pathway caused by a mutation in the UROS gene which encodes for uroporphyrinogen-III synthase. This enzyme catalyzes the dehydrogenation of hydroxymethylbilane into water and uroporphyrinogen III, which will undergo several more reactions to eventually form heme. This disorder is characterized by a large accumulation of porphyrins in the feces, urine and plasma, as well as in bones and teeth, potentially giving them a darkened or red appearance. Symptoms of this disorder include sensitivity to light, leading to potential skin damage as children, which can then lead to severe deformities. Red urine and teeth can also be seen in infancy. Treatment of CEP includes limiting or eliminating exposure to the sun, blood transfusions, and potentially bone marrow transplants or stem cell treatment. It is estimated that CEP affects less than 1 in 1,000,000 individuals.
References
Congenital Erythropoietic Porphyria (CEP) or Gunther Disease References
[Uniprot: P10746](http://www.uniprot.org/uniprot/P10746)
[OMIM: Entry 263700](http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=263700)
Kappas, A.; Sassa, S.; Anderson, K. E. The porphyrias. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S.: The Metabolic Basis of Inherited Disease. New York: McGraw-Hill (pub.) (5th ed.) (1983) p.1301-1384.
Bishop DF, Johansson A, Phelps R, Shady AA, Ramirez MC, Yasuda M, Caro A, Desnick RJ: Uroporphyrinogen III synthase knock-in mice have the human congenital erythropoietic porphyria phenotype, including the characteristic light-induced cutaneous lesions. Am J Hum Genet. 2006 Apr;78(4):645-58. doi: 10.1086/502667. Epub 2006 Feb 9.
Pubmed: 16532394
Desnick RJ, Astrin KH: Congenital erythropoietic porphyria: advances in pathogenesis and treatment. Br J Haematol. 2002 Jun;117(4):779-95.
Pubmed: 12060112
Xu W, Astrin KH, Desnick RJ: Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene. Hum Mutat. 1996;7(3):187-92. doi: 10.1002/(SICI)1098-1004(1996)7:3<187::AID-HUMU1>3.0.CO;2-8.
Pubmed: 8829650
Erwin A, Balwani M, Desnick RJ: Congenital Erythropoietic Porphyria
Pubmed: 24027798
Ged C, Mendez M, Robert E, Lalanne M, Lamrissi-Garcia I, Costet P, Daniel JY, Dubus P, Mazurier F, Moreau-Gaudry F, de Verneuil H: A knock-in mouse model of congenital erythropoietic porphyria. Genomics. 2006 Jan;87(1):84-92. doi: 10.1016/j.ygeno.2005.08.018. Epub 2005 Nov 28.
Pubmed: 16314073
Porphyrin Metabolism References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Bishop DF: Two different genes encode delta-aminolevulinate synthase in humans: nucleotide sequences of cDNAs for the housekeeping and erythroid genes. Nucleic Acids Res. 1990 Dec 11;18(23):7187-8. doi: 10.1093/nar/18.23.7187.
Pubmed: 2263504
Bawden MJ, Borthwick IA, Healy HM, Morris CP, May BK, Elliott WH: Sequence of human 5-aminolevulinate synthase cDNA. Nucleic Acids Res. 1987 Oct 26;15(20):8563. doi: 10.1093/nar/15.20.8563.
Pubmed: 3671094
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Pubmed: 15489334
Zhao Y, Wang L, Shen HB, Wang ZX, Wei QY, Chen F: Association between delta-aminolevulinic acid dehydratase (ALAD) polymorphism and blood lead levels: a meta-regression analysis. J Toxicol Environ Health A. 2007 Dec;70(23):1986-94. doi: 10.1080/15287390701550946.
Pubmed: 17966070
Wetmur JG, Kaya AH, Plewinska M, Desnick RJ: Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning. Am J Hum Genet. 1991 Oct;49(4):757-63.
Pubmed: 1716854
Wetmur JG, Bishop DF, Cantelmo C, Desnick RJ: Human delta-aminolevulinate dehydratase: nucleotide sequence of a full-length cDNA clone. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7703-7. doi: 10.1073/pnas.83.20.7703.
Pubmed: 3463993
Raich N, Romeo PH, Dubart A, Beaupain D, Cohen-Solal M, Goossens M: Molecular cloning and complete primary sequence of human erythrocyte porphobilinogen deaminase. Nucleic Acids Res. 1986 Aug 11;14(15):5955-68. doi: 10.1093/nar/14.15.5955.
Pubmed: 2875434
Grandchamp B, De Verneuil H, Beaumont C, Chretien S, Walter O, Nordmann Y: Tissue-specific expression of porphobilinogen deaminase. Two isoenzymes from a single gene. Eur J Biochem. 1987 Jan 2;162(1):105-10. doi: 10.1111/j.1432-1033.1987.tb10548.x.
Pubmed: 3816774
Yoo HW, Warner CA, Chen CH, Desnick RJ: Hydroxymethylbilane synthase: complete genomic sequence and amplifiable polymorphisms in the human gene. Genomics. 1993 Jan;15(1):21-9. doi: 10.1006/geno.1993.1005.
Pubmed: 7916736
Tsai SF, Bishop DF, Desnick RJ: Human uroporphyrinogen III synthase: molecular cloning, nucleotide sequence, and expression of a full-length cDNA. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7049-53. doi: 10.1073/pnas.85.19.7049.
Pubmed: 3174619
Aizencang G, Solis C, Bishop DF, Warner C, Desnick RJ: Human uroporphyrinogen-III synthase: genomic organization, alternative promoters, and erythroid-specific expression. Genomics. 2000 Dec 1;70(2):223-31. doi: 10.1006/geno.2000.6373.
Pubmed: 11112350
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
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.
Pubmed: 8644733
Romeo PH, 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. 1986 Jul 25;261(21):9825-31.
Pubmed: 3015909
Delfau-Larue MH, Martasek P, Grandchamp B: Coproporphyrinogen oxidase: gene organization and description of a mutation leading to exon 6 skipping. Hum Mol Genet. 1994 Aug;3(8):1325-30. doi: 10.1093/hmg/3.8.1325.
Pubmed: 7987309
Puy H, Robreau AM, Rosipal R, Nordmann Y, Deybach JC: Protoporphyrinogen oxidase: complete genomic sequence and polymorphisms in the human gene. Biochem Biophys Res Commun. 1996 Sep 4;226(1):226-30. doi: 10.1006/bbrc.1996.1337.
Pubmed: 8806618
Whatley SD, Puy H, Morgan RR, Robreau AM, Roberts AG, Nordmann Y, Elder GH, Deybach JC: Variegate porphyria in Western Europe: identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation. Am J Hum Genet. 1999 Oct;65(4):984-94. doi: 10.1086/302586.
Pubmed: 10486317
Nishimura K, Taketani S, Inokuchi H: Cloning of a human cDNA for protoporphyrinogen oxidase by complementation in vivo of a hemG mutant of Escherichia coli. J Biol Chem. 1995 Apr 7;270(14):8076-80. doi: 10.1074/jbc.270.14.8076.
Pubmed: 7713909
Levi S, Corsi B, Bosisio M, Invernizzi R, Volz A, Sanford D, Arosio P, Drysdale J: A human mitochondrial ferritin encoded by an intronless gene. J Biol Chem. 2001 Jul 6;276(27):24437-40. doi: 10.1074/jbc.C100141200. Epub 2001 Apr 25.
Pubmed: 11323407
Langlois d'Estaintot B, Santambrogio P, Granier T, Gallois B, Chevalier JM, Precigoux G, Levi S, Arosio P: Crystal structure and biochemical properties of the human mitochondrial ferritin and its mutant Ser144Ala. J Mol Biol. 2004 Jul 2;340(2):277-93. doi: 10.1016/j.jmb.2004.04.036.
Pubmed: 15201052
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