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Titolo:
A mouse model of familial porphyria cutanea tarda
Autore:
Phillips, JD; Jackson, LK; Bunting, M; Franklin, MR; Thomas, KR; Levy, JE; Andrews, NC; Kushner, JP;
Indirizzi:
Univ Utah, Sch Med, Dept Med, Salt Lake City, UT 84132 USA Univ Utah SaltLake City UT USA 84132 t Med, Salt Lake City, UT 84132 USA Univ Utah, Sch Med, Dept Pharmacol & Toxicol, Salt Lake City, UT 84132 USAUniv Utah Salt Lake City UT USA 84132 xicol, Salt Lake City, UT 84132 USA Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA Harvard Univ BostonMA USA 02115 Sch Med, Dept Med, Boston, MA 02115 USA Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 h Med, Dept Pediat, Boston, MA 02115 USA Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA Childrens Hosp Boston MA USA 02115 iv Hematol Oncol, Boston, MA 02115 USA Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA Childrens Hosp Boston MA USA 02115 Hughes Med Inst, Boston, MA 02115 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 1, volume: 98, anno: 2001,
pagine: 259 - 264
SICI:
0027-8424(20010102)98:1<259:AMMOFP>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN UROPORPHYRINOGEN DECARBOXYLASE; EMBRYONIC STEM-CELLS; HEPATOERYTHROPOIETIC-PORPHYRIA; MUTATION; IDENTIFICATION; SEQUENCE; CDNA; HEMOCHROMATOSIS; DELETION; CLONING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Kushner, JP Univ Utah, Sch Med, Div Hematol 4C416, 50 N Med Dr, Salt Lake City, UT 84132 USA Univ Utah 50 N Med Dr Salt Lake City UT USA 84132 UT 84132 USA
Citazione:
J.D. Phillips et al., "A mouse model of familial porphyria cutanea tarda", P NAS US, 98(1), 2001, pp. 259-264

Abstract

Approximately one-third of patients with porphyria cutanea tarda (PCT), the most common porphyria in humans, inherit a single mutant allele of the uroporphyrinogen decarboxylase (URO-D) gene. PCT associated with URO-D mutations is designated familial PCT. The phenotype is characterized by a photosensitive dermatosis with hepatic accumulation and urinary excretion of uroporphyrin and hepta-carboxylic porphyrins. Most heterozygotes for URO-D mutations do not express a porphyric phenotype unless hepatic siderosis is present. Hemochromatosis gene (HFE) mutations are frequently found when the phenotype is expressed. We used homologous recombination to disrupt one allele of murine URO-D. URO-D+/- mice had half-wild type (wt) URO-D protein and enzymatic activity in all tissues but did not accumulate hepatic porphyrins, indicating that half-normal URO-D activity is not rate limiting. When URO-D/- mice were injected with iron-dextran and given drinking water containing delta -aminolevulinic acid for 21 days, hepatic porphyrins accumulated, and hepatic URO-D activity was reduced to 20% of wt. We bred mice homozygousfor an HFE gene disruption (HFE-/-) to URO-D+/- mice, generating mice withthe URO-D+/-/HFE-/- genotype. These animals developed a porphyric phenotype by 14 weeks of age without ALA supplementation, and URO-D activity was reduced to 14% of wt. These data indicate that iron overload alone is sufficient to reduce URO-D activity to rate-limiting levels in URO-D+/- mice. The URO-D+/- mouse serves as an excellent model of familial PCT and affords theopportunity to define the mechanism by which iron influences URO-D activity.

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Documento generato il 25/09/20 alle ore 00:30:46