RBCC Red Blood Cell Collection

UROS [Confidence: low (only semi-automatic identification from reviews)]
Uroporphyrinogen-III synthase; UROIIIS; UROS; 4.2.1.75 (Hydroxymethylbilane hydrolyase [cyclizing]; Uroporphyrinogen-III cosynthase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P10746
ID HEM4_HUMAN Reviewed; 265 AA.
AC P10746; B2RC13; D3DRF7; Q9H2T1;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Uroporphyrinogen-III synthase;
DE Short=UROIIIS;
DE Short=UROS;
DE EC=4.2.1.75;
DE AltName: Full=Hydroxymethylbilane hydrolyase [cyclizing];
DE AltName: Full=Uroporphyrinogen-III cosynthase;
GN Name=UROS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3174619; DOI=10.1073/pnas.85.19.7049;
RA Tsai S.-F., Bishop D.F., Desnick R.J.;
RT "Human uroporphyrinogen III synthase: molecular cloning, nucleotide
RT sequence, and expression of a full-length cDNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:7049-7053(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=11112350; DOI=10.1006/geno.2000.6373;
RA Aizencang G., Solis C., Bishop D.F., Warner C., Desnick R.J.;
RT "Human uroporphyrinogen-III synthase: genomic organization,
RT alternative promoters, and erythroid-specific expression.";
RL Genomics 70:223-231(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP REVIEW ON VARIANTS.
RX PubMed=8829650;
RX DOI=10.1002/(SICI)1098-1004(1996)7:3<187::AID-HUMU1>3.3.CO;2-N;
RA Xu W., Astrin K.H., Desnick R.J.;
RT "Molecular basis of congenital erythropoietic porphyria: mutations in
RT the human uroporphyrinogen III synthase gene.";
RL Hum. Mutat. 7:187-192(1996).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS), CATALYTIC ACTIVITY, SUBUNIT,
RP MUTAGENESIS OF SER-63; ARG-65; THR-103; GLU-127; TYR-168; SER-197;
RP LYS-220; THR-227 AND THR-228, AND CHARACTERIZATION OF VARIANT ALA-62.
RX PubMed=11689424; DOI=10.1093/emboj/20.21.5832;
RA Mathews M.A., Schubert H.L., Whitby F.G., Alexander K.J., Schadick K.,
RA Bergonia H.A., Phillips J.D., Hill C.P.;
RT "Crystal structure of human uroporphyrinogen III synthase.";
RL EMBO J. 20:5832-5839(2001).
RN [9]
RP VARIANTS CEP LEU-53 AND ARG-73.
RX PubMed=2331520;
RA Deybach J.-C., de Verneuil H., Boulechfar S., Grandchamp B.,
RA Nordmann Y.;
RT "Point mutations in the uroporphyrinogen III synthase gene in
RT congenital erythropoietic porphyria (Gunther's disease).";
RL Blood 75:1763-1765(1990).
RN [10]
RP VARIANTS CEP PHE-4; ARG-73 AND MET-228.
RX PubMed=1733834; DOI=10.1007/BF00197267;
RA Boulechfar S., da Silva V., Deybach J.-C., Nordmann Y., Grandchamp B.,
RA de Verneuil H.;
RT "Heterogeneity of mutations in the uroporphyrinogen III synthase gene
RT in congenital erythropoietic porphyria.";
RL Hum. Genet. 88:320-324(1992).
RN [11]
RP VARIANTS CEP ALA-62; VAL-66; ARG-73 AND MET-228.
RX PubMed=1737856; DOI=10.1172/JCI115637;
RA Warner C.A., Yoo H.-W., Roberts A.G., Desnick R.J.;
RT "Congenital erythropoietic porphyria: identification and expression of
RT exonic mutations in the uroporphyrinogen III synthase gene.";
RL J. Clin. Invest. 89:693-700(1992).
RN [12]
RP VARIANTS CEP CYS-19; PHE-82; ALA-99; VAL-104 AND SER-225.
RX PubMed=7860775; DOI=10.1172/JCI117742;
RA Xu W., Warner C.A., Desnick R.J.;
RT "Congenital erythropoietic porphyria: identification and expression of
RT 10 mutations in the uroporphyrinogen III synthase gene.";
RL J. Clin. Invest. 95:905-912(1995).
RN [13]
RP VARIANT CEP PRO-212.
RX PubMed=8655129; DOI=10.1007/s004390050093;
RA Tanigawa K., Bensidhoum M., Takamura N., Namba H., Yamashita S.,
RA de Verneuil H., Ged C.;
RT "A novel point mutation in congenital erythropoietic porphyria in two
RT members of Japanese family.";
RL Hum. Genet. 97:557-560(1996).
RN [14]
RP VARIANT CEP PHE-3, AND CHARACTERIZATION OF VARIANT CEP PHE-3.
RX PubMed=9188670;
RX DOI=10.1002/(SICI)1096-8628(19970613)70:3<299::AID-AJMG16>3.0.CO;2-G;
RA Takamura N., Hombrados I., Tanigawa K., Namba H., Nagayama Y.,
RA de Verneuil H., Yamashita S.;
RT "Novel point mutation in the uroporphyrinogen III synthase gene causes
RT congenital erythropoietic porphyria of a Japanese family.";
RL Am. J. Med. Genet. 70:299-302(1997).
RN [15]
RP VARIANT CEP ARG-188.
RX PubMed=9834209;
RA Tezcan I., Xu W., Gurgey A., Tuncer M., Cetin M., Oener C., Yetgin S.,
RA Ersoy F., Aizencang G., Astrin K.H., Desnick R.J.;
RT "Congenital erythropoietic porphyria successfully treated by
RT allogeneic bone marrow transplantation.";
RL Blood 92:4053-4058(1998).
RN [16]
RP VARIANT CEP ARG-73.
RX PubMed=9803266; DOI=10.1046/j.1469-1809.1998.6230225.x;
RA Frank J., Wang X., Lam H.M., Aita V.M., Jugert F.K., Goerz G.,
RA Merk H.F., Poh-Fitzpatrick M.B., Christiano A.M.;
RT "C73R is a hotspot mutation in the uroporphyrinogen III synthase gene
RT in congenital erythropoietic porphyria.";
RL Ann. Hum. Genet. 62:225-230(1998).
RN [17]
RP VARIANT CEP THR-129, AND CHARACTERIZATION OF VARIANT CEP THR-129.
RX PubMed=11121156; DOI=10.1046/j.1523-1747.2000.0202a.x;
RA Rogounovitch T., Takamura N., Hombrados I., Morel C., Tanaka T.,
RA Kameyoshi Y., Shimizu-Yoshida Y., de Verneuil H., Yamashita S.;
RT "Congenital erythropoietic porphyria: a novel homozygous mutation in a
RT Japanese patient.";
RL J. Invest. Dermatol. 115:1156-1156(2000).
RN [18]
RP VARIANTS CEP THR-69; ARG-73; TRP-188; 210-GLU-LEU-211 DELINS
RP HIS-ILE-GLN-SER-GLN-ALA-GLN-SER-GLN-ALA-GLN-ASP-ASN; SER-219 AND
RP MET-228, AND CHARACTERIZATION OF VARIANTS CEP THR-69; TRP-188 AND
RP SER-219.
RX PubMed=12060141; DOI=10.1046/j.1365-2141.2002.03558.x;
RA Shady A.A., Colby B.R., Cunha L.F., Astrin K.H., Bishop D.F.,
RA Desnick R.J.;
RT "Congenital erythropoietic porphyria: identification and expression of
RT eight novel mutations in the uroporphyrinogen III synthase gene.";
RL Br. J. Haematol. 117:980-987(2002).
RN [19]
RP VARIANT CEP PRO-47, AND CHARACTERIZATION OF VARIANT CEP PRO-47.
RX PubMed=15304101; DOI=10.1111/j.0022-202X.2004.23401.x;
RA Ged C., Megarbane H., Chouery E., Lalanne M., Megarbane A.,
RA de Verneuil H.;
RT "Congenital erythropoietic porphyria: report of a novel mutation with
RT absence of clinical manifestations in a homozygous mutant sibling.";
RL J. Invest. Dermatol. 123:589-591(2004).
RN [20]
RP VARIANT CEP GLN-248.
RX PubMed=21653323; DOI=10.1182/blood-2011-03-342873;
RA To-Figueras J., Ducamp S., Clayton J., Badenas C., Delaby C., Ged C.,
RA Lyoumi S., Gouya L., de Verneuil H., Beaumont C., Ferreira G.C.,
RA Deybach J.C., Herrero C., Puy H.;
RT "ALAS2 acts as a modifier gene in patients with congenital
RT erythropoietic porphyria.";
RL Blood 118:1443-1451(2011).
RN [21]
RP VARIANT CEP PRO-237.
RX PubMed=22350154; DOI=10.1007/s11033-012-1497-z;
RA Moghbeli M., Maleknejad M., Arabi A., Abbaszadegan M.R.;
RT "Mutational analysis of uroporphyrinogen III cosynthase gene in
RT Iranian families with congenital erythropoietic porphyria.";
RL Mol. Biol. Rep. 39:6731-6735(2012).
CC -!- FUNCTION: Catalyzes cyclization of the linear tetrapyrrole,
CC hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the
CC branch point for the various sub-pathways leading to the wide
CC diversity of porphyrins. Porphyrins act as cofactors for a
CC multitude of enzymes that perform a variety of processes within
CC the cell such as methionine synthesis (vitamin B12) or oxygen
CC transport (heme).
CC -!- CATALYTIC ACTIVITY: Hydroxymethylbilane = uroporphyrinogen III +
CC H(2)O.
CC -!- PATHWAY: Porphyrin-containing compound metabolism; protoporphyrin-
CC IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate:
CC step 3/4.
CC -!- SUBUNIT: Monomer.
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Congenital erythropoietic porphyria (CEP) [MIM:263700]:
CC Porphyrias are inherited defects in the biosynthesis of heme,
CC resulting in the accumulation and increased excretion of
CC porphyrins or porphyrin precursors. They are classified as
CC erythropoietic or hepatic, depending on whether the enzyme
CC deficiency occurs in red blood cells or in the liver. The
CC manifestations of CEP are heterogeneous, ranging from nonimmune
CC hydrops fetalis due to severe hemolytic anemia in utero to milder,
CC later onset forms, which have only skin lesions due to cutaneous
CC photosensitivity in adult life. The deficiency in UROS activity
CC results in the non-enzymatic conversion of hydroxymethylbilane
CC (HMB) into the uroporphyrinogen-I isomer. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Note=Severe congenital erythropoietic porphyria is
CC associated with non-immune hydrops fetalis, a generalized edema of
CC the fetus with fluid accumulation in the body cavities due to non-
CC immune causes. Non-immune hydrops fetalis is not a diagnosis in
CC itself but a symptom, a feature of many genetic disorders, and the
CC end-stage of a wide variety of disorders.
CC -!- SIMILARITY: Belongs to the uroporphyrinogen-III synthase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/UROS";
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DR EMBL; J03824; AAA60273.1; -; mRNA.
DR EMBL; AF230665; AAG36795.1; -; mRNA.
DR EMBL; AH010036; AAG36794.1; -; Genomic_DNA.
DR EMBL; AK314896; BAG37410.1; -; mRNA.
DR EMBL; AL360176; CAI12087.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW49221.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW49222.1; -; Genomic_DNA.
DR EMBL; BC002573; AAH02573.1; -; mRNA.
DR PIR; A40483; A40483.
DR RefSeq; NP_000366.1; NM_000375.2.
DR UniGene; Hs.501376; -.
DR PDB; 1JR2; X-ray; 1.84 A; A/B=1-265.
DR PDBsum; 1JR2; -.
DR ProteinModelPortal; P10746; -.
DR SMR; P10746; 1-260.
DR IntAct; P10746; 2.
DR MINT; MINT-2863993; -.
DR STRING; 9606.ENSP00000357775; -.
DR ChEMBL; CHEMBL4433; -.
DR PhosphoSite; P10746; -.
DR DMDM; 122849; -.
DR PaxDb; P10746; -.
DR PRIDE; P10746; -.
DR DNASU; 7390; -.
DR Ensembl; ENST00000368786; ENSP00000357775; ENSG00000188690.
DR Ensembl; ENST00000368797; ENSP00000357787; ENSG00000188690.
DR GeneID; 7390; -.
DR KEGG; hsa:7390; -.
DR UCSC; uc001liw.4; human.
DR CTD; 7390; -.
DR GeneCards; GC10M127467; -.
DR HGNC; HGNC:12592; UROS.
DR HPA; HPA044038; -.
DR MIM; 263700; phenotype.
DR MIM; 606938; gene.
DR neXtProt; NX_P10746; -.
DR Orphanet; 79277; Congenital erythropoietic porphyria.
DR PharmGKB; PA37222; -.
DR eggNOG; COG1587; -.
DR HOGENOM; HOG000007209; -.
DR HOVERGEN; HBG000492; -.
DR InParanoid; P10746; -.
DR KO; K01719; -.
DR OMA; DKGIAME; -.
DR OrthoDB; EOG7K3TMH; -.
DR PhylomeDB; P10746; -.
DR BioCyc; MetaCyc:HS07569-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR UniPathway; UPA00251; UER00320.
DR EvolutionaryTrace; P10746; -.
DR GenomeRNAi; 7390; -.
DR NextBio; 28934; -.
DR PRO; PR:P10746; -.
DR ArrayExpress; P10746; -.
DR Bgee; P10746; -.
DR CleanEx; HS_UROS; -.
DR Genevestigator; P10746; -.
DR GO; GO:0005829; C:cytosol; NAS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0048037; F:cofactor binding; IEA:Ensembl.
DR GO; GO:0004852; F:uroporphyrinogen-III synthase activity; IDA:UniProtKB.
DR GO; GO:0071418; P:cellular response to amine stimulus; IEA:Ensembl.
DR GO; GO:0071243; P:cellular response to arsenic-containing substance; IEA:Ensembl.
DR GO; GO:0006783; P:heme biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006782; P:protoporphyrinogen IX biosynthetic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
DR GO; GO:0006780; P:uroporphyrinogen III biosynthetic process; IDA:UniProtKB.
DR InterPro; IPR003754; 4pyrrol_synth_uPrphyn_synth.
DR Pfam; PF02602; HEM4; 1.
DR SUPFAM; SSF69618; SSF69618; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disease mutation; Heme biosynthesis; Lyase; Polymorphism;
KW Porphyrin biosynthesis; Reference proteome.
FT CHAIN 1 265 Uroporphyrinogen-III synthase.
FT /FTId=PRO_0000135251.
FT VARIANT 3 3 V -> F (in CEP; no residual activity).
FT /FTId=VAR_021615.
FT VARIANT 4 4 L -> F (in CEP).
FT /FTId=VAR_003674.
FT VARIANT 19 19 Y -> C (in CEP).
FT /FTId=VAR_003675.
FT VARIANT 47 47 S -> P (in CEP; less than 3% wild-type
FT activity; severe cutaneous lesions).
FT /FTId=VAR_021616.
FT VARIANT 53 53 P -> L (in CEP; no detectable activity;
FT severe phenotype).
FT /FTId=VAR_003676.
FT VARIANT 62 62 T -> A (in CEP; no detectable activity
FT according to PubMed:1737856, while it
FT does not affect enzymatic activity
FT according to PubMed:11689424;
FT dbSNP:rs28941775).
FT /FTId=VAR_003677.
FT VARIANT 66 66 A -> V (in CEP; residual activity; mild
FT phenotype; dbSNP:rs28941774).
FT /FTId=VAR_003678.
FT VARIANT 69 69 A -> T (in CEP; less than 2% wild-type
FT activity; moderately-severe phenotype).
FT /FTId=VAR_021617.
FT VARIANT 73 73 C -> R (in CEP; frequent mutation in
FT Western countries; no detectable
FT activity; severe phenotype).
FT /FTId=VAR_003679.
FT VARIANT 82 82 V -> F (in CEP; high residual activity;
FT mild phenotype; dbSNP:rs121908016).
FT /FTId=VAR_003680.
FT VARIANT 99 99 V -> A (in CEP).
FT /FTId=VAR_003681.
FT VARIANT 104 104 A -> V (in CEP; residual activity).
FT /FTId=VAR_003682.
FT VARIANT 124 124 K -> R (in dbSNP:rs17153561).
FT /FTId=VAR_049345.
FT VARIANT 129 129 I -> T (in CEP; no residual activity).
FT /FTId=VAR_021618.
FT VARIANT 171 171 V -> G (in dbSNP:rs17173752).
FT /FTId=VAR_049346.
FT VARIANT 188 188 G -> R (in CEP; less than 5% wild-type
FT activity).
FT /FTId=VAR_013558.
FT VARIANT 188 188 G -> W (in CEP; less than 2% wild-type
FT activity; mild phenotype).
FT /FTId=VAR_021619.
FT VARIANT 210 211 EL -> HIQSQAQSQAQDN (in CEP).
FT /FTId=VAR_021620.
FT VARIANT 212 212 S -> P (in CEP; no residual activity).
FT /FTId=VAR_003683.
FT VARIANT 219 219 I -> S (in CEP; less than 2% wild-type
FT activity; moderately-severe phenotype).
FT /FTId=VAR_021621.
FT VARIANT 225 225 G -> S (in CEP).
FT /FTId=VAR_003684.
FT VARIANT 228 228 T -> M (in CEP; no detectable activity).
FT /FTId=VAR_003685.
FT VARIANT 237 237 L -> P (in CEP).
FT /FTId=VAR_067318.
FT VARIANT 248 248 P -> Q (in CEP).
FT /FTId=VAR_066247.
FT MUTAGEN 63 63 S->A: Does not affect enzymatic activity.
FT MUTAGEN 65 65 R->A: Slightly affects enzymatic
FT activity.
FT MUTAGEN 103 103 T->A: Slightly affects enzymatic
FT activity.
FT MUTAGEN 127 127 E->A: Does not affect enzymatic activity.
FT MUTAGEN 168 168 Y->F: Impairs enzymatic activity.
FT MUTAGEN 197 197 S->A: Does not affect enzymatic activity.
FT MUTAGEN 220 220 K->A: Does not affect enzymatic activity.
FT MUTAGEN 227 227 T->A: Does not affect enzymatic activity.
FT MUTAGEN 228 228 T->A: Impairs enzymatic activity.
FT STRAND 2 9
FT HELIX 18 24
FT TURN 25 27
FT STRAND 29 34
FT STRAND 36 40
FT HELIX 43 50
FT HELIX 53 55
FT STRAND 57 61
FT HELIX 64 76
FT HELIX 80 86
FT HELIX 88 93
FT STRAND 94 98
FT HELIX 101 109
FT HELIX 122 130
FT STRAND 139 144
FT HELIX 146 148
FT HELIX 151 156
FT TURN 157 159
FT STRAND 162 166
FT STRAND 168 172
FT HELIX 176 187
FT STRAND 191 197
FT HELIX 198 212
FT HELIX 213 218
FT STRAND 219 225
FT HELIX 226 234
FT STRAND 240 242
FT STRAND 244 247
FT HELIX 248 258
SQ SEQUENCE 265 AA; 28628 MW; CEF171401361F61E CRC64;
MKVLLLKDAK EDDCGQDPYI RELGLYGLEA TLIPVLSFEF LSLPSFSEKL SHPEDYGGLI
FTSPRAVEAA ELCLEQNNKT EVWERSLKEK WNAKSVYVVG NATASLVSKI GLDTEGETCG
NAEKLAEYIC SRESSALPLL FPCGNLKREI LPKALKDKGI AMESITVYQT VAHPGIQGNL
NSYYSQQGVP ASITFFSPSG LTYSLKHIQE LSGDNIDQIK FAAIGPTTAR ALAAQGLPVS
CTAESPTPQA LATGIRKALQ PHGCC
//

MIM 263700
*RECORD*
*FIELD* NO
263700
*FIELD* TI
#263700 PORPHYRIA, CONGENITAL ERYTHROPOIETIC
;;CEP;;
GUNTHER DISEASE;;
UROPORPHYRINOGEN III SYNTHASE DEFICIENCY;;
read moreUROS DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because congenital
erythropoietic porphyria (CEP) is caused by homozygous or compound
heterozygous mutation in the uroporphyrinogen III synthase gene (UROS;
606938) on chromosome 10q.

DESCRIPTION

The porphyrias are diseases caused by defects in heme synthesis,
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 (Gross et al., 2000).

Desnick and Astrin (2002) provided a comprehensive review of congenital
erythropoietic porphyria pathogenesis and treatment.

One patient with a phenotype suggestive of congenital erythropoietic
anemia was found to have a mutation in the GATA1 gene (305371.0010) that
affected UROS expression (see XLTT, 314050).

CLINICAL FEATURES

The most dramatic form of genetic porphyria is that which was early
recognized as an inborn error of metabolism by Gunther (Dean, 1972). It
is associated with lifelong overproduction of series I porphyrins which
circulate and are deposited in many tissues, causing light-sensitization
and severe damage to skin beginning in childhood. Blistering and
scarring of exposed areas may lead to mutilating deformity.
Hypertrichosis is sometimes severe. Uroporphyrin I and coproporphyrin I
are found in plasma, red blood cells, urine, and feces. Red urine may be
observed from infancy, and the teeth become stained red. Hemolytic
anemia, an additional complication, may be helped by splenectomy (Meyer
and Schmid, 1978). Gunther called this condition congenital
haematoporphyria. Watson et al. (1956) renamed it erythropoietic
porphyria.

Nordmann et al. (1990) described an infant girl who had inherited
Gunther disease from both parents and coproporphyria (121300) from her
mother. In the newborn period the patient developed intense jaundice
with hepatosplenomegaly associated with diffuse bleeding and
thrombocytopenia. On the tenth day of life the baby showed a rash with
blisters on the backs of the hands and red discoloration of the urine.
Porphyria was established by high levels of porphyrins in the urine,
feces, and blood. During the next 2 years transfusions were required
because of hemolysis. Skin photosensitivity with blistering, fragility,
hypertrichosis of the face, and erythrodontia developed. Somatic and
mental development were poor. Each of the 2 forms of porphyria was
established by enzymatic study. The biologic features of coproporphyria
predominated during the first days of life.

- Adult-Onset Form

Deybach et al. (1981) described a mild form of congenital erythropoietic
porphyria with onset in adulthood. Rank et al. (1990) reported what they
stated to be the sixth report of adult onset of congenital
erythropoietic porphyria. A beneficial effect of hematin therapy was
observed. Murphy et al. (1995) described a man who developed cutaneous
signs of congenital erythropoietic porphyria at the age of 65 years, 5
years after the onset of symptomatic thrombocytopenia. Persistent
thrombocytopenia unresponsive to corticosteroids and immunoglobulin
necessitated a splenectomy. Photosensitivity, hemolytic anemia, and
hypersplenism are prominent features of adult-onset Gunther disease and
thrombocytopenia had been documented in several cases. In the patient
reported by Murphy et al. (1995), platelet sequestration studies
implicated the spleen as the major site of platelet consumption;
however, platelet-associated IgG antibodies were also present. Four
weeks following splenectomy, the platelet count rose and stabilized and
remained stable 1 year later.

INHERITANCE

Congenital erythropoietic porphyria is an autosomal recessive condition.
Most other forms of genetic porphyria are dominantly inherited (121300,
176000, 176100, 176200). Acute hepatic porphyria is apparently recessive
(see 125270).

As would be expected for an enzyme deficiency, autosomal recessive
inheritance of congenital erythropoietic porphyria is well documented,
with multiple sib cases and increased consanguinity in parents; obligate
heterozygotes have intermediate levels of uroporphyrinogen III
cosynthetase activity (Romeo et al., 1970). The patient described by
Nordmann et al. (1990) was an Algerian girl, born to first-cousin
parents. The patient described by Pollack and Rosenthal (1994) was the
offspring of first-cousin parents and showed organomegaly, hemolytic
anemia, thrombocytopenia, and cutaneous blisters.

DIAGNOSIS

Tsai et al. (1987) described an enzymatic method for the diagnosis of
heterozygotes and homozygotes. Pollack and Rosenthal (1994) illustrated
the diagnosis of this disorder in a neonate by examining a urine-soaked
diaper under Wood's light. Urine and feces of patients contain increased
levels of uroporphyrinogen I and coproporphyrinogen I (Gross et al.,
2000).

- Prenatal Diagnosis

Uroporphyrinogen III cosynthetase is expressed in cultured amniotic
cells so that prenatal diagnosis is possible (Deybach et al., 1980).
Since the chromosomal assignment and molecular genetics of congenital
erythropoietic porphyria have been determined, prenatal diagnosis by
genetic analysis is possible (Lim and Cohen, 1999).

CLINICAL MANAGEMENT

Piomelli et al. (1986) showed that by suppressing erythropoiesis with
high-level transfusions, one can prevent symptoms of this disorder. As
their patient grew older, transfusion requirements to keep the
hematocrit above the desired 39% increased, but the requirement was
reduced by splenectomy, indicating that the spleen is a factor in the
hemolytic anemia. Iron overload was mitigated by slow infusions of
deferoxamine.

Pimstone et al. (1987) reviewed the various forms of therapy that have
been used in this disorder: splenectomy, hypertransfusion, and orally
administered sorbents such as charcoal and cholestyramine, which bind
porphyrins and retard intestinal absorption of endogenous porphyrins
excreted into the gut lumen. In a man in his mid-fifties, Pimstone et
al. (1987) found that charcoal was more effective than cholestyramine
and that treatment with charcoal for 9 months lowered porphyrin levels
in plasma and skin and resulted in a complete clinical remission.
Measurements of subnormal red cell uroporphyrinogen decarboxylase
activity and urinary, fecal, and plasma porphyrin analyses in this
patient and his 7 children indicated classic features of familial
porphyria cutanea tarda (176100). They concluded that their patient had
an atypical form of congenital erythropoietic porphyria similar to that
described by Eriksen and Eriksen (1977). The authors pointed out that
the usefulness of charcoal therapy in photocutaneous porphyrias other
than this form and in reversing the hepatic lesion in patients with
protoporphyric liver disease remains to be explored. Subtle
complications of long-term charcoal ingestion, such as nutrient
malabsorption or systemic absorption of charcoal, require further
evaluation.

Tezcan et al. (1998) stated that allogeneic bone marrow transplantation
(BMT) had been performed in 3 patients with CEP. They demonstrated
long-term biochemical and clinical effectiveness of BMT performed in a
severely affected, transfusion-dependent 18-month-old female with CEP.
Three years post-BMT, the recipient had normal hemoglobin, markedly
reduced urinary uroporphyrin excretion, and no cutaneous lesions despite
unlimited exposure to sunlight. The patient was homoallelic for a novel
UROS missense mutation, G188R (606938.0010), that expressed less than 5%
of mean normal activity of the enzyme in E. coli, consistent with her
transfusion dependency. Tezcan et al. (1998) emphasized that because the
clinical severity of CEP is highly variable, ranging from nonimmune
hydrops fetalis to milder, later-onset forms with only cutaneous
lesions, it is important to genotype newly diagnosed infants to select
severely affected patients for BMT. The long-term effectiveness of BMT
in their patient provided the rationale for future hematopoietic stem
cell gene therapy in severely affected patients.

PATHOGENESIS

Deficiency of the enzyme uroporphyrinogen III cosynthetase was
demonstrated in peripheral blood (Levin, 1968; Romeo and Levin, 1969)
and cultured fibroblasts (Romeo et al., 1970). Kappas et al. (1983)
stated that the mechanism of the hemolytic anemia in CEP was poorly
understood; it obviously creates a vicious cycle by leading to
exaggerated erythropoiesis. Petry, the famous CEP patient studied by
Gunther and by Hans Fischer (pictured by Kappas et al., 1983), was
thought to have died of pernicious anemia and splenomegaly but the
published autopsy findings were said to be more suggestive of hemolytic
anemia.

MOLECULAR GENETICS

In a patient with Gunther disease, Deybach et al. (1990) and Warner et
al. (1990) found a mutation in codon 73 of the uroporphyrinogen III
synthase gene (606938.0001). Xu et al. (1996) stated that 17 mutations
in the UROS gene had been reported as the basis of CEP: 11 missense, 1
nonsense, 2 mRNA splicing defects, 1 deletion, and 2 coding region
insertions.

POPULATION GENETICS

Congenital erythropoietic porphyria is exceedingly rare; as of 1997,
about 130 cases had been reported (Fritsch et al., 1997).

ANIMAL MODEL

An analogous disorder has been described in several animal species; the
best-delineated animal model is in cattle, in which autosomal recessive
inheritance is well demonstrated (Watson et al., 1956; Levin, 1968), but
congenital erythropoietic porphyria is said to be dominant in swine and
in cats (Glenn et al., 1968).

All fox squirrels (Sciurus niger) exhibit a species characteristic
resembling congenital erythropoietic porphyria in humans (Levin and
Flyger, 1971, 1973). Flyger and Levin (1977) noted that this appears to
be the only mammalian species that possesses this characteristic except
as a rare pathologic condition. However, the condition in fox squirrels
is accompanied by neither skin lesions nor hemolytic anemia.

Bishop et al. (2006) generated knockin mice with 3 missense mutations in
the Uros gene. Mice homozygous for all 3 mutations were fetal lethals,
except for those homozygous for a spontaneous recombinant allele. Mice
homozygous for the recombinant allele had 20% of wildtype URO-synthase
activity in erythrocytes, apparently sufficient for fetal development
and survival. The mice showed marked porphyrin I isomer accumulation in
erythrocytes, bone, tissues, and excreta and had fluorescent
erythrodontia, hemolytic anemia with reticulocytosis and extramedullary
erythropoiesis, and, notably, the characteristic light-induced cutaneous
involvement. These mice provided insight into why congenital
erythropoietic porphyria is an erythroid porphyria and should facilitate
studies of the disease pathogenesis and therapeutic endeavors.

Robert-Richard et al. (2008) studied the feasibility of gene therapy in
a murine model of congenital erythropoietic porphyria.
Lentivirus-mediated transfer of the human UROS cDNA into hematopoietic
stem cells (HSCs) from the mouse model Uros(mut248) resulted in a
complete and long-term enzymatic, metabolic, and phenotypic correction
of the disease, favored by a survival advantage of corrected red blood
cells. The results demonstrated the cure of this mouse model of CEP at a
moderate transduction level, thus providing proof of concept of a gene
therapy in this disease by transplanting genetically modified
hematopoietic stem cells.

*FIELD* SA
Marver and Schmid (1972); Romeo et al. (1970)
*FIELD* RF
1. Bishop, D. F.; Johansson, A.; Phelps, R.; Shady, A. A.; Ramirez,
M. C. M.; Yasuda, M.; Caro, A.; Desnick, R. J.: Uroporphyrinogen
III synthase knock-in mice have the human congenital erythropoietic
porphyria phenotype, including the characteristic light-induced cutaneous
lesions. Am. J. Hum. Genet. 78: 645-658, 2006.

2. Dean, G.: The Porphyrias. Philadelphia: J. B. Lippincott (pub.)
(2nd ed.): 1972.

3. Desnick, R. J.; Astrin, K. H.: Congenital erythropoietic porphyria:
advances in pathogenesis and treatment. (Review) Brit. J. Haemat. 117:
779-795, 2002.

4. Deybach, J.-C.; 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 75:
1763-1765, 1990.

5. Deybach, J.-C.; de Verneuil, H.; Phung, N.; Nordmann, Y.; Puissant,
A.; Boffety, B.: Congenital erythropoietic porphyria (Gunther's disease):
enzymatic studies on two cases of late onset. J. Lab. Clin. Med. 97:
551-558, 1981.

6. Deybach, J.-C.; Grandchamp, B.; Grelier, M.; Nordmann, Y.; Boue,
J.; Boue, A.; de Berranger, P.: Prenatal exclusion of congenital
erythropoietic porphyria (Gunther's disease) in a fetus at risk. Hum.
Genet. 53: 217-221, 1980.

7. Eriksen, L.; Eriksen, N.: Urinary excretion of position isomers
of penta- and hexa-carboxylated porphyrins belonging to the isomer
III series in a case of congenital erythropoietic porphyria. Scand.
J. Clin. Lab. Invest. 37: 357-361, 1977.

8. Flyger, V.; Levin, E. Y.: Animal model of human disease: congenital
erythropoietic porphyria. Am. J. Path. 87: 269-272, 1977.

9. Fritsch, C.; Bolsen, K.; Ruzicka, T.; Goerz, G.: Congenital erythropoietic
porphyria. J. Am. Acad. Derm. 36: 594-610, 1997.

10. Glenn, B. L.; Glenn, H. G.; Omtvedt, I. T.: Congenital porphyria
in the domestic cat (Felis catus): preliminary investigations on inheritance
pattern. Am. J. Vet. Res. 29: 1653-1657, 1968.

11. Gross, U.; Hoffmann, G. F.; Doss, M. O.: Erythropoietic and hepatic
porphyrias. J. Inherit. Metab. Dis. 23: 641-661, 2000.

12. 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. Pp. 1301-1384.

13. Levin, E. Y.: Uroporphyrinogen III cosynthetase in bovine erythropoietic
porphyria. Science 161: 907-908, 1968.

14. Levin, E. Y.; Flyger, V.: Uroporphyrinogen III cosynthetase activity
in the fox squirrel (Sciurus niger). Science 174: 59-60, 1971.

15. Levin, E. Y.; Flyger, V.: Erythropoietic porphyria of the fox
squirrel Sciurus niger. J. Clin. Invest. 52: 96-105, 1973.

16. Lim, H. W.; Cohen, J. L.: The cutaneous porphyrias. Semin. Cutan.
Med. Surg. 18: 285-292, 1999.

17. Marver, H. S.; Schmid, R.: The porphyrias.In: Stanbury, J. B.;
Wyngaarden, J. B.; Fredrickson, D. S.: The Metabolic Basis of Inherited
Disease. New York: McGraw-Hill (pub.) (3rd ed.): 1972. Pp. 1087-1140.

18. Meyer, U.; Schmid, R.: The porphyrias.In: Stanbury, J. B.; Wyngaarden,
J. B.; Fredrickson, D. S.: The Metabolic Basis of Inherited Disease.
New York: McGraw-Hill (pub.) (4th ed.): 1978. Pp. 1166-1220.

19. Murphy, A.; Gibson, G.; Elder, G. H.; Otridge, B. A.; Murphy,
G. M.: Adult-onset congenital erythropoietic porphyria (Gunther's
disease) presenting with thrombocytopenia. J. Royal Soc. Med. 88:
357P-358P, 1995.

20. Nordmann, Y.; Amram, D.; Deybach, J. C.; Phung, L. N.; Lesbros,
D.: Coexistent hereditary coproporphyria and congenital erythropoietic
porphyria (Gunther disease). J. Inherit. Metab. Dis. 13: 687-691,
1990.

21. Pimstone, N. R.; Gandhi, S. N.; Mukerji, S. K.: Therapeutic efficacy
of oral charcoal in congenital erythropoietic porphyria. New Eng.
J. Med. 316: 390-393, 1987.

22. Piomelli, S.; Poh-Fitzpatrick, M. B.; Seaman, C.; Skolnick, L.
M.; Berdon, W. E.: Complete suppression of the symptoms of congenital
erythropoietic porphyria by long-term treatment with high-level transfusions. New
Eng. J. Med. 314: 1029-1031, 1986.

23. Pollack, S. S.; Rosenthal, M. S.: Diaper diagnosis of porphyria. New
Eng. J. Med. 330: 114 only, 1994.

24. Rank, J. M.; Straka, J. G.; Weimer, M. K.; Bossenmaier, I.; Taddeini,
L.; Bloomer, J. R.: Hematin therapy in late onset congenital erythropoietic
porphyria. Brit. J. Haemat. 75: 617-618, 1990.

25. Robert-Richard, E.; Moreau-Gaudry, F.; Lalanne, M.; Lamrissi-Garcia,
I.; Cario-Andre, M.; Guyonnet-Duperat, V.; Taine, L.; Ged, C.; de
Verneuil, H.: Effective gene therapy of mice with congenital erythropoietic
porphyria is facilitated by a survival advantage of corrected erythroid
cells. Am. J. Hum. Genet. 82: 113-124, 2008.

26. Romeo, G.; Glenn, B. L.; Levin, E. Y.: Uroporphyrinogen III cosynthetase
in asymptomatic carriers of congenital erythropoietic porphyria. Biochem.
Genet. 4: 719-726, 1970.

27. Romeo, G.; Kaback, M. M.; Levin, E. Y.: Uroporphyrinogen III
cosynthetase activity in fibroblasts from patients with congenital
erythropoietic porphyria. Biochem. Genet. 4: 659-664, 1970.

28. Romeo, G.; Levin, E. Y.: Uroporphyrinogen III cosynthetase in
human congenital erythropoietic porphyria. Proc. Nat. Acad. Sci. 63:
856-863, 1969.

29. Tezcan, I.; Xu, W.; Gurgey, A.; Tuncer, M.; Cetin, M.; Oner, C.;
Yetgin, S.; Ersoy, F.; Aizencang, G.; Astrin, K. H.; Desnick, R. J.
: Congenital erythropoietic porphyria successfully treated by allogeneic
bone marrow transplantation. Blood 92: 4053-4058, 1998.

30. Tsai, S.-F.; Bishop, D. F.; Desnick, R. J.: Coupled-enzyme and
direct assays for uroporphyrinogen III synthase activity in human
erythrocytes and cultured lymphoblasts: enzymatic diagnosis of heterozygotes
and homozygotes with congenital erythropoietic porphyria. Anal. Biochem. 166:
120-133, 1987.

31. Warner, C. A.; Yoo, H. W.; Tsai, S.-F.; Roberts, A. G.; Desnick,
R. J.: Congenital erythropoietic porphyria: characterization of the
genomic structure and identification of mutations in the uroporphyrinogen
III synthase gene. Am. J. Hum. Genet. 47 (suppl.): A83 only, 1990.

32. Watson, C. J.; Perman, V.; Spurrell, F. A.; Hoyt, H. H.; Schwartz,
S.: Some studies of the comparative biology of human and bovine porphyria
erythropoietica. Trans. Assoc. Am. Phys. 71: 196-209, 1956.

33. Xu, W.; Astrin, K. H.; Desnick, R. J.: Molecular basis of congenital
erythropoietic porphyria: mutations in the human uroporphyrinogen
III synthase gene. Hum. Mutat. 7: 187-192, 1996.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature

HEAD AND NECK:
[Eyes];
Conjunctivitis;
Corneal scarring;
[Mouth];
Red stained teeth (erythrodontia)

ABDOMEN:
[Biliary tract];
Porphyrin-rich gallstones;
[Spleen];
Splenomegaly

SKELETAL:
Osteolysis;
Osteopenia;
[Spine];
Vertebral compression or collapse;
[Limbs];
Pathologic fractures;
[Hands];
Contractures of the fingers

SKIN, NAILS, HAIR:
[Skin];
Photosensitivity;
Blistering;
Scarring;
Mutilating skin deformity;
Pseudoscleroderma;
Hyperpigmentation;
Hypopigmentation;
[Hair];
Hypertrichosis;
Alopecia;
Loss of eyelashes;
Loss of eyebrows

HEMATOLOGY:
Hemolytic anemia;
Thrombocytopenia

LABORATORY ABNORMALITIES:
Uroporphyrin I and coproporphyrin I are found in plasma, red blood
cells, urine, and feces;
Uroporphyrinogen III cosynthase (URO cosynthase) deficiency in blood
and fibroblasts;
Pink urine

MISCELLANEOUS:
Onset at birth;
Rare disorder

MOLECULAR BASIS:
Caused by mutation in the uroporphyrinogen III cosynthase gene (UROS,
606938.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 3/3/2006
Ada Hamosh - reviewed: 1/4/2001
Kelly A. Przylepa - revised: 2/28/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 06/26/2012
joanna: 2/1/2007
ckniffin: 3/3/2006
joanna: 3/14/2005
ckniffin: 5/17/2002
joanna: 1/4/2001
kayiaros: 2/28/2000

*FIELD* CN
Victor A. McKusick - updated: 2/19/2008
Victor A. McKusick - updated: 3/15/2006
Victor A. McKusick - updated: 5/2/2003
Victor A. McKusick - updated: 8/15/2002
Cassandra L. Kniffin - reorganized: 5/14/2002
Cassandra L. Kniffin - updated: 5/14/2002
Victor A. McKusick - updated: 2/16/1999
Victor A. McKusick - updated: 1/25/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 07/02/2012
ckniffin: 6/28/2012
wwang: 6/13/2011
terry: 11/3/2010
carol: 4/16/2009
alopez: 2/26/2008
terry: 2/19/2008
alopez: 3/21/2006
terry: 3/15/2006
cwells: 5/5/2003
terry: 5/2/2003
tkritzer: 8/20/2002
tkritzer: 8/16/2002
terry: 8/15/2002
carol: 5/14/2002
ckniffin: 5/14/2002
mgross: 2/22/1999
mgross: 2/18/1999
terry: 2/16/1999
mgross: 2/9/1999
mgross: 2/8/1999
terry: 1/25/1999
dkim: 7/24/1998
terry: 7/2/1996
terry: 6/27/1996
mark: 7/28/1995
davew: 8/31/1994
mimadm: 4/18/1994
carol: 1/26/1994
carol: 6/10/1992
carol: 6/9/1992

MIM 606938
*RECORD*
*FIELD* NO
606938
*FIELD* TI
*606938 UROPORPHYRINOGEN III SYNTHASE; UROS
;;UROIIIS
*FIELD* TX

DESCRIPTION

Uroporphyrinogen III synthase is also known as hydroxymethylbilane
read morehydrolyase (cyclizing) (EC 4.2.1.75). It is the fourth enzyme in the
8-enzyme pathway in the conversion of glycine and succinyl-CoA to heme.
It is responsible for the conversion of the linear tetrapyrrole,
hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III
(Tsai et al., 1988).

CLONING

Tsai et al. (1988) cloned a full-length cDNA encoding uroporphyrinogen
III synthase by screening a human adult liver cDNA library. The sequence
encoded a 265-amino acid protein with a molecular mass of 28,607 Da. By
Northern blot, 5-prime RACE, and multiple-tissue array analyses,
Aizencang et al. (2000) demonstrated the presence of 2 UROS transcripts:
an erythroid-specific transcript and a housekeeping transcript, which
was present at low levels in all 76 tissues tested, with highest
abundance in skeletal and heart muscle and in the caudate nucleus and
amygdala.

GENE STRUCTURE

Aizencang et al. (2000) determined the structure of the 34-kb UROS gene.
It contains alternative erythroid-specific and housekeeping promoters
and a coding sequence comprising 9 exons.

Meng et al. (2003) determined that the 5-prime end of the UROS gene
abuts the BCCIP gene (611883) on the opposite strand in a head-to-head
manner. BCCIP and UROS share a functional intergenic bidirectional
promoter that contains binding sites for various transcription factors.

MAPPING

Using cloned cDNA, Astrin et al. (1991) mapped the UROS gene to
10q25.2-q26.3. The assignment to chromosome 10 was also found when UROS
sequences were specifically amplified by PCR from genomic DNA from
independent panels of human-rodent somatic cell hybrids; there was 100%
concordance for the presence of the human UROS PCR product and human
chromosome 10.

Xu et al. (1995) cloned the mouse gene and mapped it to chromosome 7 in
a region of conserved synteny with human chromosome 10.

MOLECULAR GENETICS

In a patient with Gunther disease, Deybach et al. (1990) and Warner et
al. (1990) identified a mutation in codon 73 of the uroporphyrinogen III
synthase gene (606938.0001). Xu et al. (1995) used a rapid sequencing
technique to analyze all 10 exons of the UROS gene from 20 unrelated
patients with congenital erythropoietic porphyria (CEP; 263700). Of the
14 mutations identified, 10 were new. The new mutations included 6
missense mutations, a nonsense mutation, a frameshift mutation, and 2
splicing mutations.

Xu et al. (1996) stated that 17 mutations in the UROS gene had been
reported as the basis of CEP: 11 missense, 1 nonsense, 2 mRNA splicing
defects, 1 deletion, and 2 coding region insertions. With the exception
of C73R (606938.0001) and L4F (606938.0006) which occurred in 29.6% and
9.3% of the 54 mutant alleles studied, respectively, most mutations had
been identified in 1 or a few unrelated families. Analyses had revealed
only 83% of the causative mutations. The V82F (606938.0009) mutation,
resulting from a G-to-T transversion of the last nucleotide of exon 4,
caused both a missense mutation and an aberrantly spliced RNA
transcript. Prokaryotic expression of the mutant UROS alleles identified
those with significant residual activity, thereby permitting
genotype/phenotype predictions in this clinically heterogeneous
disorder.

Shady et al. (2002) identified 8 novel mutations in the UROS gene in
cases of CEP. Expression studies in E. coli showed that only 1 of the 4
novel missense mutations identified, glu81 to asp (E81D; 606938.0011),
expressed significant enzymatic activity (30% of expressed wildtype
activity), which was thermolabile. In addition, RT-PCR studies
demonstrated that E81D, which altered the penultimate nucleotide in exon
4, impaired splicing and caused approximately 85% exon 4 skipping. The
phenotype in 7 probands studied varied from mild, cutaneous only, to
severe, transfusion-dependent.

In a mutation analysis of 40 unrelated patients with CEP, Desnick et al.
(1998) identified both UROS mutant alleles in 29 patients and only 1 of
the mutant alleles in 11 patients (11 unidentified mutations in 80
alleles, or 13.8%). Solis et al. (2001) sequenced the erythroid-specific
promoter of the UROS gene in 6 patients with a single previously
undefined allele and identified 4 novel mutations clustered in a 20-bp
region: a -70T-C transition (606938.0013) in a putative GATA1 consensus
binding element; a -76G-A transition (606938.0014); a -86C-A
transversion (606938.0015) in 3 unrelated patients; and a -90C-A
transversion (606938.0016) in a putative CP2 binding motif. They
inserted these mutant sequences into luciferase reporter constructs.
When transfected into K562 erythroid cells, these constructs yielded
greatly reduced reporter activity as compared with the wildtype
promoter. Electrophoretic mobility shift assays indicated that the
-70T-C transition altered GATA1 binding, whereas the adjacent -76G-A
transition did not. Similarly, the -90C-A transversion altered CP2
binding, whereas the -86C-A transversion did not. Thus, these 4
pathogenic erythroid promoter mutations impaired erythroid-specific
transcription, caused CEP, and identified functionally important GATA1
and CP2 transcriptional binding elements for erythroid-specific heme
biosynthesis.

ANIMAL MODEL

Ged et al. (2006) stated that knockout of the Uros gene in mice results
in nonviable blastocysts. By gene targeting, they developed a knockin
model that reproduced the human pro248-to-gln (P248Q; 606938.0020)
mutation, which leads to severe UROS deficiency. Heterozygous mice
appeared normal, but homozygous mutant mice were hypotrophic at birth
and produced red urine and showed erythrodontia in the first weeks of
life. Homozygous mutant mice also showed photosensitivity and
hepatosplenomegaly, and uroporphyrin (99% type I isomer) accumulated in
urine. Total porphyrins were increased in erythrocytes and feces, while
Uros enzymatic activity was below 1% of the normal level in tissues
analyzed, closely mimicking CEP in humans.

*FIELD* AV
.0001
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, CYS73ARG

In a patient with Gunther disease (263700), Deybach et al. (1990) found
heterozygosity for a T-to-C change in codon 73 (cysteine to arginine;
C73R) and a C-to-T change in codon 53 (proline to leucine, or P53L;
606938.0002). Warner et al. (1990) likewise demonstrated the C73R
mutation. Warner et al. (1992) found this mutation in 8 of 21 unrelated
CEP patients (21% of CEP alleles). Boulechfar et al. (1992) concluded
that the C73R mutation is the most frequent one found in CEP.

According to Tanigawa et al. (1995), the C73R mutation accounts for over
40% of all mutant UROS alleles in CEP. Frank et al. (1998) investigated
3 separate families with CEP from different ethnic backgrounds.
Haplotype analysis using 2 microsatellite markers that closely flank the
UROS gene on 10q24, spanning a region of 4 cM, showed that the C73R
mutation occurred on different haplotypes in all 4 disease chromosomes
studied. The results were considered consistent with the hypothesis that
C73R is a hotspot mutation for CEP, and does not represent wide
dispersion of a single ancestral mutant C73R allele.

Fortian et al., (2011) found that the C73R mutation destabilized the
UROIIIS protein via irreversible unfolding and aggregation, followed by
proteasomal degradation. At physiologic temperature, wildtype UROIIIS
had a half-life of 2.5 days, whereas the C73R mutant protein had a
half-life of 15 minutes. Treatment of cells with a proteasome inhibitor
restored mutant protein levels, and the restored mutant protein showed
50% of wildtype enzymatic activity.

.0002
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, PRO53LEU

In a patient with Gunther disease (263700), Deybach et al. (1990) found
homozygosity for the pro53-to-leu mutation that was found in another
patient in a genetic compound; see 606938.0001.

.0003
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, ALA66VAL

In a patient with congenital erythropoietic porphyria (263700), Warner
et al. (1990, 1992) demonstrated a 197C-T transition resulting in a
substitution of valine for alanine at position 66. The patient was a
compound heterozygote for this and the cys73-to-arg mutation
(606938.0001).

.0004
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, THR62ALA

Warner et al. (1992) found a 184A-G transition that predicted a
thr-to-ala substitution at residue 62.

.0005
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, THR228MET

Warner et al. (1992) demonstrated a 683C-T transition that resulted in a
thr-to-met replacement at residue 228. Warner et al. (1992) performed
genotype-phenotype correlations: the A66V/C73R, T228M/C73R, and
C73R/C73R genotypes were associated with mild, moderately severe, and
severe disease, respectively. Boulechfar et al. (1992) also identified
this mutation.

.0006
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, LEU4PHE

In a patient with congenital erythropoietic porphyria (263700),
Boulechfar et al. (1992) identified a C-to-T transition at nucleotide
10, which was responsible for substitution of phenylalanine for
leucine-4.

.0007
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, 98-BP DEL, NT148

In a patient with congenital erythropoietic porphyria (263700),
Boulechfar et al. (1992) demonstrated deletion of nucleotides 148-245.
The deleted segment included the sites of 2 previously described point
mutations, pro53-to-leu (606938.0002) and cys73-to-arg (606938.0001).

.0008
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, 80-BP INS

In a patient with congenital erythropoietic porphyria (263700),
Boulechfar et al. (1992) identified an 80-bp insertion in the UROS gene
that created a frameshift at codon 221, leading to a new sequence of 45
amino acids at the C-terminal part of the protein.

.0009
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, VAL82PHE

In a patient with congenital erythropoietic porphyria (263700), Xu et
al. (1995) found a missense mutation changing residue 82 from a valine
to a phenylalanine. The mutation occurred adjacent to the 5-prime donor
site of intron 4 and resulted in approximately 54% aberrantly spliced
transcripts with exon 4 deleted. Thus, this novel exonic single-base
substitution caused 2 lesions: an amino acid substitution and an
aberrantly spliced transcript. The mutation causing V82F is a G-to-T
transversion of the last nucleotide of exon 4.

.0010
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, GLY188ARG

In an 18-month-old female with CEP (263700), Tezcan et al. (1998)
identified a G-to-A transition at nucleotide 562 in the UROS gene,
predicting a gly188-to-arg substitution. Both parents were found to be
carriers of the mutation.

.0011
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, GLU81ASP

In an Indian patient with mild, cutaneous-only CEP (263700), the
offspring of nonconsanguineous parents, Shady et al. (2002) found
compound heterozygosity for glu81-to-asp (E81D) and gly188-to-trp
(G188W) mutations. The E81D mutation resulted from a 243A-T
transversion. The G188W mutation resulted from a 562G-T transversion in
exon 9, which predicted the substitution of a larger, hydrophobic
tryptophan for an uncharged glycine. The same codon is involved in the
G188R mutation (606938.0010).

.0012
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, GLY188TRP

See 606938.0011 and Shady et al. (2002).

.0013
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, -70T-C

In a French male fetus with congenital erythropoietic porphyria (263700)
and nonimmune hydrops fetalis (236750), Solis et al. (2001) identified
compound heterozygosity for 2 mutations in the UROS gene: a -70T-C
transition in the erythroid promoter and C73R (606938.0001). In
addition, they identified heterozygosity for a -224T-C transition, which
was present in approximately 4% of 200 unrelated Caucasian alleles. The
healthy father was heterozygous for the -70T-C mutation and homozygous
for the -224C polymorphism.

.0014
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, -76G-A

In a 49-year-old American male with mild, cutaneous-only CEP (263700),
Solis et al. (2001) identified compound heterozygosity for 2 mutations
in the UROS gene: a -76G-A transition in the erythroid promoter and C73R
(606938.0001).

.0015
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, -86C-A

In 3 unrelated patients with mild, cutaneous-only CEP (263700), Solis et
al. (2001) identified compound heterozygosity for 2 mutations in the
UROS gene: a -86C-A transversion in the erythroid promoter and a second
allele, which was different in each patient. The second allele was a
C73R mutation (606938.0001) in a 19-year-old Scandinavian female, a
donor splice site at intron 2 (606938.0018) in a 60-year-old
Scandinavian female originally studied by Xu et al. (1995), and a 1-bp
insertion, 398insG (606938.0019), in a 44-year-old English male.

.0016
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, -90C-A

In a 33-year-old English male with moderately severe
transfusion-dependent CEP (263700), Solis et al. (2001) identified
compound heterozygosity for 2 mutations in the UROS gene: a -90C-A
transversion in the erythroid promoter and G225S (606938.0017).

.0017
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, GLY225SER

See 606938.0016 and Solis et al. (2001).

.0018
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, IVS2DS, G-A, +1

See 606938.0015, Xu et al. (1995), and Solis et al. (2001).

.0019
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, 1-BP INS, 398G

See 606938.0015 and Solis et al. (2001).

.0020
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, PRO248GLN

Fontanellas et al. (1996) identified a C-to-A transversion at nucleotide
743 in exon 10 of the UROS gene, resulting in a pro248-to-gln (P248Q)
substitution, in 3 patients from 2 Spanish families with severe
congenital erythropoietic porphyria (263700). All 3 patients also
carried the cys73-to-arg mutation (C73R; 606938.0001).

.0021
PORPHYRIA, CONGENITAL ERYTHROPOIETIC
UROS, IVS9, T-G, -31

In 3 unrelated patients with congenital erythropoietic porphyria
(263700), Bishop et al. (2010) identified a homozygous T-to-G
transversion in intron 9 of the UROS gene 31 bp upstream from exon 10
(661-31T-G). The mutation was not found in 100 control alleles. The
mutation resulted in the generation of several alternatively spliced
longer transcripts containing excess nucleotides from intron 9,
including 1 or more sequences of 81, 165, or 277 bp. The 81-bp insertion
was in-frame and resulted in a functional transcript that contributed
only about 0.2% residual activity, whereas the other alternative
transcripts resulted in premature termination. RT-PCR of patient
lymphoblasts showed about 10% normal 1.5-kb transcript with 27% abnormal
transcript, and residual UROS activity was about 14%. Two of the
patients were men of Ashkenazi descent. One was severely affected from
birth with marked photosensitivity, hepatosplenomegaly, and anemia. The
other required red cell transfusions, but had significant periods during
adolescence without treatment. He had marked cutaneous involvement
resulting from unprotected exposure to sunlight. The third patient was a
44-year-old man of Lebanese descent whose parents were consanguineous.
He had had chronic, progressive skin ulcerations since adolescence that
eventually disfigured his sun-exposed face and hands; he also had
anemia. All patients had markedly elevated levels of uroporphyrin I in
the urine.

*FIELD* RF
1. Aizencang, G.; Solis, C.; Bishop, D. F.; Warner, C.; Desnick, R.
J.: Human uroporphyrinogen-III synthase: genomic organization, alternative
promoters, and erythroid-specific expression. Genomics 70: 223-231,
2000.

2. Astrin, K. H.; Warner, C. A.; Yoo, H.-W.; Goodfellow, P. J.; Tsai,
S.-F.; Desnick, R. J.: Regional assignment of the human uroporphyrinogen
III synthase (UROS) gene to chromosome 10q25.2-q26.3. Hum. Genet. 87:
18-22, 1991.

3. Bishop, D. F.; Schneider-Yin, X.; Clavero, S.; Yoo, H.-W.; Minder,
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uroporphyrinogen III synthase branchpoint mutation reveals underlying
wild-type alternatively spliced transcripts. Blood 115: 1062-1069,
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320-324, 1992.

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7. Fontanellas, A.; Bensidhoum, M.; Enriquez de Salamanca, R.; Tirado,
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9. Frank, J.; Wang, X.; Lam, H.-M.; Aita, V. M.; Jugert, F. K.; Goerz,
G.; Merk, H. F.; Poh-Fitzpatrick, M. B.; Christiano, A. M.: C73R
is a hotspot mutation in the uroporphyrinogen III synthase gene in
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1998.

10. Ged, C.; Mendez, M.; Robert, E.; Lalanne, M.; Lamrissi-Garcia,
I.; Costet, P.; Daniel, J. Y.; Dubus, P.; Mazurier, F.; Moreau-Gaudry,
F.; de Verneuil, H.: A knock-in mouse model of congenital erythropoietic
porphyria. Genomics 87: 84-92, 2006.

11. Meng, X.; Liu, J.; Shen, Z.: Genomic structure of the human BCCIP
gene and its expression in cancer. Gene 302: 139-146, 2003.

12. Shady, A. A.; Colby, B. R.; Cunha, L. F.; Astrin, K. H.; Bishop,
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13. Solis, C.; Aizencang, G. I.; Astrin, K. H.; Bishop, D. F.; Desnick,
R. J.: Uroporphyrinogen III synthase erythroid promoter mutations
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14. Tanigawa, K.; Takamura, N.; Yamashita, S.: Congenital erythropoietic
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15. Tezcan, I.; Xu, W.; Gurgey, A.; Tuncer, M.; Cetin, M.; Oner, C.;
Yetgin, S.; Ersoy, F.; Aizencang, G.; Astrin, K. H.; Desnick, R. J.
: Congenital erythropoietic porphyria successfully treated by allogeneic
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16. Tsai, S.-F.; Bishop, D. F.; Desnick, R. J.: Human uroporphyrinogen
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17. Warner, C. A.; Yoo, H.-W.; Roberts, A. G.; Desnick, R. J.: Congenital
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693-700, 1992.

18. Warner, C. A.; Yoo, H. W.; Tsai, S.-F.; Roberts, A. G.; Desnick,
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20. Xu, W.; Kozak, C. A.; Desnick, R. J.: Uroporphyrinogen-III synthase:
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*FIELD* CN
Cassandra L. Kniffin - updated: 9/12/2011
Patricia A. Hartz - updated: 6/10/2011
Patricia A. Hartz - updated: 3/7/2008
Matthew B. Gross - updated: 2/27/2006
Patricia A. Hartz - updated: 2/9/2006
Victor A. McKusick - updated: 6/11/2003
Victor A. McKusick - updated: 9/20/2002

*FIELD* CD
Cassandra L. Kniffin: 5/14/2002

*FIELD* ED
carol: 09/20/2013
carol: 8/5/2013
carol: 9/20/2011
ckniffin: 9/12/2011
mgross: 8/29/2011
terry: 6/10/2011
mgross: 3/7/2008
mgross: 2/27/2006
terry: 2/9/2006
carol: 8/13/2003
carol: 7/11/2003
tkritzer: 7/9/2003
terry: 6/11/2003
tkritzer: 9/25/2002
tkritzer: 9/23/2002
carol: 9/20/2002
carol: 5/14/2002
ckniffin: 5/14/2002