{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T08:23:35Z","timestamp":1777623815927,"version":"3.51.4"},"reference-count":35,"publisher":"American Society of Hematology","issue":"12","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Functional consequences of 12 mutations\u201410 missense, 1 splicing defect, and 1 frameshift mutation\u2014were characterized in the uroporphyrinogen decarboxylase (URO-D) gene found in Utah pedigrees with familial porphyria cutanea tarda (F-PCT). All but one mutation altered a restriction site in the URO-D gene, permitting identification of affected relatives using a combination of polymerase chain reaction and restriction enzyme digestion. In a bacterial expression system, 3 of the missense mutants were found in inclusion bodies, but 7 were expressed as soluble proteins. Enzymatic activity of soluble, recombinant mutant URO-D genes ranged from 29% to 94% of normal. URO-D mRNA levels in Epstein-Barr\u2013virus transformed cells derived from patients were normal (with the exception of the frameshift mutation) even though protein levels were lower than normal, suggesting that missense mutations generally cause unstable URO-Ds in vivo. The crystal structures of 3 mutant URO-Ds were solved, and the structural consequences of the mutations were defined. All missense mutations reported here and by others were mapped to the crystal structure of URO-D, and structural effects were predicted. These studies define structural and functional consequences of URO-D mutations occurring in patients with F-PCT.<\/jats:p>","DOI":"10.1182\/blood.v98.12.3179","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:40Z","timestamp":1027774000000},"page":"3179-3185","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":30,"title":["Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase"],"prefix":"10.1182","volume":"98","author":[{"given":"John D.","family":"Phillips","sequence":"first","affiliation":[{"name":"From the Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiffany L.","family":"Parker","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi L.","family":"Schubert","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank G.","family":"Whitby","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher P.","family":"Hill","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James P.","family":"Kushner","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine and Biochemistry, University of Utah School of Medicine, Salt Lake City."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"key":"2020021221091821700_B1","first-page":"505","article-title":"Heme biosynthesis, the porphyrias, and the liver.","volume-title":"The Liver: Biology and Pathobiology.","author":"Wyckoff","year":"1994","edition":"3rd ed."},{"key":"2020021221091821700_B2","first-page":"2103","article-title":"The porphyrias.","volume":"2","author":"Kappas","year":"1995","journal-title":"The Metabolic and Molecular Bases of Inherited Disease."},{"key":"2020021221091821700_B3","first-page":"712","article-title":"Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria.","volume":"58","author":"Moran-Jimenez","year":"1996","journal-title":"Am J Hum Genet."},{"key":"2020021221091821700_B4","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/1523-1747.ep12374134","article-title":"Molecular defects of uroporphyrinogen decarboxylase in a patient with mild hepatoerythropoietic porphyria.","volume":"102","author":"Meguro","year":"1994","journal-title":"J Invest Dermatol."},{"key":"2020021221091821700_B5","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1126\/science.3775362","article-title":"Uroporphyrinogen decarboxylase structural mutant (Gly281\u2192Glu) in a case of porphyria.","volume":"234","author":"de Verneuil","year":"1986","journal-title":"Science."},{"key":"2020021221091821700_B6","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1365-2362.1991.tb01814.x","article-title":"Identification of a new mutation responsible for hepatoerythropoietic porphyria.","volume":"21","author":"Romana","year":"1991","journal-title":"Eur J Clin Invest."},{"key":"2020021221091821700_B7","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1182\/blood.V73.4.892.892","article-title":"A point mutation in the coding region of uroporphyrinogen decarboxylase associated with familial porphyria cutanea tarda.","volume":"73","author":"Garey","year":"1989","journal-title":"Blood."},{"key":"2020021221091821700_B8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/0016-5085(93)90022-5","article-title":"Analysis of uroporphyrinogen decarboxylase complementary DNAs in sporadic porphyria cutanea tarda.","volume":"105","author":"Garey","year":"1993","journal-title":"Gastroenterology."},{"key":"2020021221091821700_B9","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1182\/blood.V88.9.3589.bloodjournal8893589","article-title":"Five new mutations in the uroporphyrinogen decarboxylase gene identified in families with cutaneous porphyria.","volume":"88","author":"McManus","year":"1996","journal-title":"Blood."},{"key":"2020021221091821700_B10","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/(SICI)1098-1004(1999)14:3<222::AID-HUMU5>3.0.CO;2-V","article-title":"Screening for mutations in the uroporphyrinogen decarboxylase gene using denaturing gradient gel electrophoresis: identification and characterization of six novel mutations associated with familial PCT.","volume":"14","author":"Christiansen","year":"1999","journal-title":"Hum Mutat."},{"key":"2020021221091821700_B11","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/(SICI)1098-1004(1999)13:5<412::AID-HUMU11>3.0.CO;2-T","article-title":"Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda [abstract].","volume":"13","author":"McManus","year":"1999","journal-title":"Hum Mutat."},{"key":"2020021221091821700_B12","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1046\/j.1523-1747.2000.00148.x","article-title":"Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda.","volume":"115","author":"Brady","year":"2000","journal-title":"J Invest Dermatol."},{"key":"2020021221091821700_B13","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1086\/302119","article-title":"Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles.","volume":"63","author":"Mendez","year":"1998","journal-title":"Am J Hum Genet."},{"key":"2020021221091821700_B14","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/1098-1004(200009)16:3<269::AID-HUMU12>3.0.CO;2-#","article-title":"Mutations in familial porphyria cutanea tarda: two novel and two previously described for hepatoerythropoietic porphyria.","volume":"16","author":"Mendez","year":"2000","journal-title":"Hum Mutat."},{"key":"2020021221091821700_B15","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1182\/blood.V95.5.1565.005k42_1565_1571","article-title":"Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda.","volume":"95","author":"Bulaj","year":"2000","journal-title":"Blood."},{"key":"2020021221091821700_B16","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1002\/hep.510270627","article-title":"Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America.","volume":"27","author":"Bonkovsky","year":"1998","journal-title":"Hepatology."},{"key":"2020021221091821700_B17","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1002\/pro.5560060624","article-title":"Characterization and crystallization of human uroporphyrinogen decarboxylase.","volume":"6","author":"Phillips","year":"1997","journal-title":"Protein Sci."},{"key":"2020021221091821700_B18","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1159\/000132139","article-title":"Assignment of uroporphyrinogen decarboxylase (UROD) to the pter-p21 region of human chromosome 1.","volume":"39","author":"McLellan","year":"1985","journal-title":"Cytogenet Cell Genet."},{"key":"2020021221091821700_B19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/BF00401245","article-title":"Assignment of human uroporphyrinogen decarboxylase (URO-D) to the p34 band of chromosome 1.","volume":"73","author":"Dubart","year":"1986","journal-title":"Hum Genet."},{"key":"2020021221091821700_B20","doi-asserted-by":"crossref","first-page":"7343","DOI":"10.1093\/nar\/15.18.7343","article-title":"Structure of the gene for uroporphyrinogen decarboxylase.","volume":"15","author":"Romana","year":"1987","journal-title":"Nucleic Acids Res."},{"key":"2020021221091821700_B21","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1093\/emboj\/17.9.2463","article-title":"Crystal structure of human uroporphyrinogen decarboxylase.","volume":"17","author":"Whitby","year":"1998","journal-title":"EMBO J."},{"key":"2020021221091821700_B22","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1093\/clinchem\/27.3.397","article-title":"Liquid-chromatographic analysis for urinary porphyrins.","volume":"27","author":"Ford","year":"1981","journal-title":"Clin Chem."},{"key":"2020021221091821700_B23","first-page":"8.4.1","article-title":"Measurement of uroporphyrinogen decarboxylase activity.","volume-title":"Current Protocols in Toxicology.","author":"Phillips","year":"1999"},{"key":"2020021221091821700_B24","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","article-title":"Processing of X-ray diffraction data collected in oscillation mode.","volume":"276","author":"Otwinowski","year":"1997","journal-title":"Methods Enzymol."},{"key":"2020021221091821700_B25","volume-title":"X-PLOR: A System for X-ray Crystallography and NMR.","author":"Brunger","year":"1996"},{"key":"2020021221091821700_B26","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1107\/S0108767390010224","article-title":"Improved methods for binding protein models in electron density maps and the location of errors in these models.","volume":"47","author":"Jones","year":"1991","journal-title":"Acta Crystallogr A."},{"key":"2020021221091821700_B27","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/BF02621085","article-title":"Human B lymphocytes immortalization by Epstein-Barr virus in the presence of cyclosporin A.","volume":"22","author":"Pelloquin","year":"1986","journal-title":"In Vitro Cell Dev Biol."},{"key":"2020021221091821700_B28","first-page":"847","article-title":"Steady-state levels of uroporphyrinogen decarboxylase mRNA in lymphoblastoid cell lines from patients with familial porphyria cutanea tarda and their relatives.","volume":"42","author":"Hansen","year":"1988","journal-title":"Am J Hum Genet."},{"key":"2020021221091821700_B29","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1126\/science.283.5410.2089","article-title":"Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A.","volume":"283","author":"Seeling","year":"1999","journal-title":"Science."},{"key":"2020021221091821700_B30","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1172\/JCI114856","article-title":"Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda.","volume":"86","author":"Garey","year":"1990","journal-title":"J Clin Invest."},{"key":"2020021221091821700_B31","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0092-8674(89)90166-9","article-title":"mRNA decay: finding the right targets.","volume":"57","author":"Brawerman","year":"1989","journal-title":"Cell."},{"key":"2020021221091821700_B32","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1093\/hmg\/8.10.1893","article-title":"Nonsense-mediated mRNA decay in health and disease.","volume":"8","author":"Frischmeyer","year":"1999","journal-title":"Hum Mol Genet."},{"key":"2020021221091821700_B33","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1073\/pnas.98.1.259","article-title":"A mouse model of familial porphyria cutanea tarda.","volume":"98","author":"Phillips","year":"2001","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021221091821700_B34","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1056\/NEJM197808102990603","article-title":"Decreased activity of hepatic uroporphyrinogen decarboxylase in sporadic porphyria cutanea tarda.","volume":"299","author":"Elder","year":"1978","journal-title":"N Engl J Med."},{"key":"2020021221091821700_B35","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0140-6736(85)90287-9","article-title":"Immunoreactive uroporphyrinogen decarboxylase in the liver in porphyria cutanea tarda.","volume":"II","author":"Elder","year":"1985","journal-title":"Lancet."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/98\/12\/3179\/1678484\/h8230103179.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/98\/12\/3179\/1678484\/h8230103179.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,13]],"date-time":"2020-02-13T02:12:48Z","timestamp":1581559968000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/98\/12\/3179\/53141\/Functional-consequences-of-naturally-occurring"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,12,1]]},"references-count":35,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2001,12,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.v98.12.3179","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2001,12,1]]}}}