title: Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP).
abstract: Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria in humans. The disorder is caused by homozygosity or compound heterozygosity for mutations of the uroporphyrinogen decarboxylase (URO-D) gene. Subnormal URO-D activity results in accumulation of uroporphyrin in the liver, which ultimately mediates the photosensitivity that clinically characterizes HEP. Two previously undescribed URO-D mutations found in a 2-year-old Caucasian boy with HEP, a maternal nonsense mutation (Gln71Stop), and a paternal missense mutation (Gly168Arg) are reported here. Recombinant Gly168Arg URO-D retained 65% of wild-type URO-D activity and studies in Epstein-Barr Virus (EBV)-transformed lymphoblasts indicated that protein levels are reduced, suggesting that the mutant protein might be subjected to accelerated turnover. The crystal structure of Gly168Arg was determined both as the apo-enzyme and with the reaction product bound. These studies revealed little distortion of the active site, but a loop containing residues 167-172 was displaced, possibly indicating small changes in the catalytic geometry or in substrate binding or increased accessibility to a cellular proteolytic pathway. A second pregnancy occurred in this family, and in utero genotyping revealed a fetus heterozygous for the maternal nonsense mutation (URO-D genotype WT/Gln71Stop). A healthy infant was born with no clinical evidence of porphyria.
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. john.phillips@hsc.utah.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.forename: Frank G
authors.initials: FG
authors.lastname: Whitby
authors.forename: Beth M
authors.initials: BM
authors.lastname: Stadtmueller
authors.forename: Corwin Q
authors.initials: CQ
authors.lastname: Edwards
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Hill
authors.forename: James P
authors.initials: JP
authors.lastname: Kushner
mesh_terms: D000328:Adult; D002461:Cell Line, Transformed; D002675:Child, Preschool; D018389:Codon, Nonsense; D003305:Coproporphyrinogens / Q000096:biosynthesis / Q000737:chemistry; D003461:Crystallography; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D017121:Porphyria, Hepatoerythropoietic / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D011296:Prenatal Diagnosis; D017434:Protein Structure, Tertiary; D014575:Uroporphyrinogen Decarboxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014577:Uroporphyrinogens / Q000737:chemistry / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D003305:Coproporphyrinogens; D014577:Uroporphyrinogens; C028026:coproporphyrinogen III; D014575:Uroporphyrinogen Decarboxylase