{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:24:59Z","timestamp":1791347099472,"version":"4.3.1"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,1,2]]},"abstract":"<jats:p>\n                    Approximately one-third of patients with porphyria cutanea tarda\n (PCT), the most common porphyria in humans, inherit a single mutant\n allele of the uroporphyrinogen decarboxylase (\n                    <jats:italic>URO-D<\/jats:italic>\n                    )\n gene. PCT associated with\n                    <jats:italic>URO-D<\/jats:italic>\n                    mutations is designated\n familial PCT. The phenotype is characterized by a photosensitive\n dermatosis with hepatic accumulation and urinary excretion of\n uroporphyrin and hepta-carboxylic porphyrins. Most heterozygotes for\n                    <jats:italic>URO-D<\/jats:italic>\n                    mutations do not express a porphyric phenotype\n unless hepatic siderosis is present. Hemochromatosis gene\n (\n                    <jats:italic>HFE<\/jats:italic>\n                    ) mutations are frequently found when the phenotype\n is expressed. We used homologous recombination to disrupt one allele of\n murine\n                    <jats:italic>URO-D<\/jats:italic>\n                    .\n                    <jats:italic>URO-D<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice\n had half-wild type (wt) URO-D protein and enzymatic activity in all\n tissues but did not accumulate hepatic porphyrins, indicating that\n half-normal URO-D activity is not rate limiting. When\n                    <jats:italic>URO-D<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice were injected with\n iron-dextran and given drinking water containing \u03b4-aminolevulinic\n acid for 21 days, hepatic porphyrins accumulated, and hepatic URO-D\n activity was reduced to 20% of wt. We bred mice homozygous for an\n                    <jats:italic>HFE<\/jats:italic>\n                    gene disruption\n (\n                    <jats:italic>HFE<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) to\n                    <jats:italic>URO-D<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice, generating mice with the\n                    <jats:italic>URO-D<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    <jats:italic>\/HFE<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    genotype. These animals developed a porphyric phenotype by 14 weeks of\n age without ALA supplementation, and URO-D activity was reduced to 14%\n of wt. These data indicate that iron overload alone is sufficient to\n reduce URO-D activity to rate-limiting levels in\n                    <jats:italic>URO-D<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice. The\n                    <jats:italic>URO-D<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mouse serves as an excellent model\n of familial PCT and affords the opportunity to define the mechanism by\n which iron influences URO-D activity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.98.1.259","type":"journal-article","created":{"date-parts":[[2012,7,30]],"date-time":"2012-07-30T13:19:48Z","timestamp":1343654388000},"page":"259-264","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":67,"title":["A mouse model of familial porphyria cutanea tarda"],"prefix":"10.1073","volume":"98","author":[{"given":"John D.","family":"Phillips","sequence":"first","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie K.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaeline","family":"Bunting","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Franklin","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk R.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne E.","family":"Levy","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy C.","family":"Andrews","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Kushner","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology and\r Toxicology, University of Utah, School of Medicine, Salt Lake City, UT\r 84132; Departments of Medicine and\r Pediatrics, Harvard Medical School, Boston, MA 02115; and\r Division of Hematology\/Oncology and\r Howard Hughes Medical Institute, Children's Hospital,\r Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,12,26]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.5.1565.005k42_1565_1571"},{"key":"e_1_3_3_2_2","first-page":"505","volume-title":"The Liver: Biology and Pathobiology","author":"Wyckoff E E","year":"1994","unstructured":"E E Wyckoff, J P Kushner The Liver: Biology and Pathobiology, eds I M Arias, J L Boyer, N Fausto, W B Jakoby, D A Schachter, D A Shafritz (Raven, New York), pp. 505\u2013527 (1994)."},{"key":"e_1_3_3_3_2","first-page":"2103","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Kappas A","year":"1995","unstructured":"A Kappas, S Sassa, R A Galbraith, Y Nordmann The Metabolic and Molecular Bases of Inherited Disease, eds C R Scriver, A L Beaudet, W S Sly, D Valle (McGraw\u2013Hill, New York) 2, 2103\u20132160 (1995)."},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007142"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510270627"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V73.4.892.892"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)32947-8"},{"key":"e_1_3_3_8_2","first-page":"548","volume":"89","author":"de Verneuil H","year":"1992","unstructured":"H de Verneuil, F Bourgeois, F de Rooij, P D Siersema, J H Wilson, B Grandchamp, Y Nordmann Hum Genet 89, 548\u2013552 (1992).","journal-title":"Hum Genet"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.1991.tb01814.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3775362"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12374134"},{"key":"e_1_3_3_12_2","first-page":"712","volume":"58","author":"Moran-Jimenez M J","year":"1996","unstructured":"M J Moran-Jimenez, C Ged, M Romana, R Enriquez-De-Salamanca, A Taieb, G Topi, L D'Alessandro, H de-Verneuil Am J Hum Genet 58, 712\u2013721 (1996).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1086\/302119"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1999)13:5<412::AID-HUMU11>3.0.CO;2-T"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1999)14:3<222::AID-HUMU5>3.0.CO;2-V"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114856"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560060624"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.9.2463"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003359900101"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196008252630807"},{"key":"e_1_3_3_21_2","first-page":"6.3.1","volume-title":"Current Protocols in Molecular Biology","author":"Strauss W M","year":"1995","unstructured":"W M Strauss Current Protocols in Molecular Biology, eds F M Ausubel, R Brent, R E Kingston, D D Moore, J G Seidman, J A Smith, K Struhl (Wiley, New York) 1, 6.3.1\u20136.3.4 (1995)."},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)67589-1"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)90022-5"},{"key":"e_1_3_3_24_2","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Maniatis T","year":"1982","unstructured":"T Maniatis, E F Fritsch, J Sambrook Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Lab. 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