2q71: Difference between revisions
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==Overview== | ==Overview== | ||
Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria in | 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. | ||
==Disease== | |||
Known diseases associated with this structure: Porphyria cutanea tarda OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176100 176100]], Porphyria, hepatoerythropoietic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176100 176100]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Uroporphyrinogen decarboxylase]] | [[Category: Uroporphyrinogen decarboxylase]] | ||
[[Category: Edwards, C | [[Category: Edwards, C Q.]] | ||
[[Category: Hill, C | [[Category: Hill, C P.]] | ||
[[Category: Kushner, J | [[Category: Kushner, J P.]] | ||
[[Category: Phillips, J | [[Category: Phillips, J D.]] | ||
[[Category: Stadtmueller, B | [[Category: Stadtmueller, B M.]] | ||
[[Category: Whitby, F | [[Category: Whitby, F G.]] | ||
[[Category: CP3]] | [[Category: CP3]] | ||
[[Category: uroporphyrinogen decarboxylase enzyme urod g168r coproporphyrinogen-iii product complex]] | [[Category: uroporphyrinogen decarboxylase enzyme urod g168r coproporphyrinogen-iii product complex]] | ||
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Revision as of 19:36, 21 February 2008
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Uroporphyrinogen Decarboxylase G168R single mutant enzyme in complex with coproporphyrinogen-III
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Porphyria cutanea tarda OMIM:[176100], Porphyria, hepatoerythropoietic OMIM:[176100]
About this StructureAbout this Structure
2Q71 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Uroporphyrinogen decarboxylase, with EC number 4.1.1.37 Full crystallographic information is available from OCA.
ReferenceReference
Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP)., Phillips JD, Whitby FG, Stadtmueller BM, Edwards CQ, Hill CP, Kushner JP, Transl Res. 2007 Feb;149(2):85-91. PMID:17240319
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