Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Protoporphyrinogen oxidase, the penultimate enzyme involved in the biosynthetic pathway for heme, catalyzes the removal of six electrons from protoporphyrinogen IX to generate protoporphyrin IX. In Escherichia coli, this enzyme is encoded by the hemG gene. In this study we examined possible alternate pathways for the oxidation of protoporphyrinogen IX to protoporphyrin IX, by isolating and investigating E. coli mutants that can still grow normally when the hemG gene is disrupted. One of these mutants was characterized in detail and had a mutation in the promoter region of the hemF gene, which encodes aerobic coproporphyrinogen oxidase, the enzyme involved in the step immediately before protoporphyrinogen oxidase. Measurement of the promoter activity of the hemF gene showed that the level of transcription was elevated by the mutation. Overexpression of a wild-type hemF gene cloned in a multicopy plasmid also restored the growth of deltahemG strain. Extracts from cells that overexpress hemF exhibited an increased ability to oxidize protoporphyrinogen IX to protoporphyrin IX. These findings suggest that the E. coli aerobic coproporphyrinogen oxidase has an intrinsic capacity to oxidize not only coproporphyrinogen III but also protoporphyrinogen IX.
Mol Gen Genet 1999 Jul
PMID:Oxidation of protoporphyrinogen IX in Escherichia coli is mediated by the aerobic coproporphyrinogen oxidase. 1048 93

Variegate porphyria is an autosomal dominant disorder of heme metabolism which results from decreased activity of the enzyme protoporphyrinogen oxidase. Clinically, the disease manifests postpubertally and is characterized by photocutaneous sensitivity and/or acute neurovisceral crises. However, in homozygous variegate porphyria, onset of the disease usually occurs in infancy with severe skin manifestations. The molecular basis of variegate porphyria in two severely affected probands in two South African families is described. Mutation detection included combined SSCP-heteroduplex analysis followed by direct sequencing. The unrelated probands both had the common R59W mutation while the other lesion was Y348C or R138P (both novel mutations), causing homozygous variegate porphyria.
Mol Genet Metab 2000 Apr
PMID:Homozygous variegate porphyria in South Africa: genotypic analysis in two cases. 1087 Aug 50

Variegate porphyria is an autosomal dominant disorder of haem metabolism resulting from reduced levels of the penultimate enzyme in the pathway, protoporphyrinogen oxidase. Here we investigate the molecular basis of variegate porphyria in four non-R59W South African families. We report the identification of the first mutation in the protoporphyrinogen oxidase gene in a black South African individual (V290M). In addition, we document three further mutations, a missense mutation (L15F), a deletion followed by a substitution [c769delG;770T > A], and a nonsense mutation (Q375X), in individuals of European or mixed ancestry. Our data provide further evidence of genetic heterogeneity in South Africa.
Mol Genet Metab 2001 May
PMID:Identification of the first variegate porphyria mutation in an indigenous black South African and further evidence for heterogeneity in variegate porphyria. 1135 Jan 88

Five single nucleotide polymorphisms (SNPs) in the protoporphyrinogen oxidase gene (PPOX) were used for inter-population comparisons of six South African populations and two non-South African Caucasian populations. Novel polymorphisms identified in the promoter region and exon 11 of the PPOX gene, as well as three known variants in exon 1 and intron 2, were analysed using single-strand conformation polymorphism (SSCP) and restriction enzyme analyses. Significant population differences were found for four of the five polymorphisms analysed. A G-to-A transition was found at nucleotide position -1081 and is the first polymorphism to be identified in the 5' promoter region of the gene. A novel A-to-C substitution at nucleotide position 3880 in exon 11 was not detected in subjects of European descent. This study represents the first inter-population comparison of allelic variation at the PPOX locus. The significant differences observed between populations demonstrate the importance of population considerations when marker association studies are performed at this locus.
Mol Cell Probes 2001 Aug
PMID:Single nucleotide polymorphisms of the protoporphyrinogen oxidase gene: inter-population heterogeneity of allelic variation. 1151 56

The murine protoporphyrinogen oxidase gene has been isolated, characterized and localized. The gene spans 4.2 kb, is comprised of 13 exons and 12 introns, and is located on chromosome 1 in band 1 H2. Analysis of 1.2 kb of the 5' upstream region revealed a promoter which is not GC rich and lacks any TATA boxes or initiator elements in the vicinity of the transcription start site. A variety of putative transcriptional element binding sequences were identified and gel shift assays support the presence of two GATA-1 sites near -760 bp as well as AP-1, AP-2, and Sp1 sites in the -1200 bp 5' flanking region. Luciferase reporter constructs transiently expressed in erythroid cell lines demonstrated erythroid-specific expression with the -1160 bp, but not with the -746 bp or -198 bp constructs. Expression in nonerythroid cells occurred maximally with -1160 bp, but was significant with -746 bp and absent with -198 bp. Expression of both housekeeping and erythroid-specific fusions in the transient expression systems was greatly decreased in the -5000 bp constructs suggesting the presence of repressor elements in the -1160 to -5000 bp region.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Characterization of the mouse protoporphyrinogen oxidase gene. 1192 49

Variegate porphyria is inherited as an autosomal dominant disease with variable penetrance. It is characterized clinically by photocutaneous sensitivity and acute neurovisceral attacks, and biochemically by abnormal porphyrin excretion in the urine and feces. While the world-wide incidence of variegate porphyria is relatively low, in South Africa it is one of the most common genetic diseases in humans. Due to the large number of patients with variegate porphyria in South Africa, and the fact that variegate porphyria is representative of both the so-called "acute" and the "photocutaneous" porphyrias, it would be valuable to have an animal model in which to study the disease. In this study we have produced a mouse model of "South African" variegate porphyria with the R59W mutation in C57/BL6 mice via targeted gene replacement. Hepatic protoporphyrinogen oxidase activity was reduced by approximately 50% in mice heterozygous for the mutation. Urine and fecal samples from these mice, in the absence of exogenous inducers of hepatic haem synthesis, contain elevated concentrations of porphyrins and porphyrin precursors in a pattern similar to that found in human variegate porphyric subjects. Bypassing the rate-limiting step in haem biosynthesis by feeding 5-aminolevulinic acid to these mice, results in an accentuated porphyrin excretory pattern characteristic of the variegate porphyric phenotype and urinary porphobilinogen is increased significantly. This initial characterization of these mice suggest that they are a good model for variegate porphyria at the biochemical level.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:A mouse model for South African (R59W) variegate porphyria: construction and initial characterization. 1192 50

The autosomal dominant disorder, variegate porphyria (VP), results from mutations in the protoporphyrinogen oxidase (PPOX) gene. We have investigated the effects of 22 disease-associated missense mutations in this gene on enzyme activity. Mutants were generated in the expression plasmid pHPPOX by site-directed mutagenesis. They were screened for PPOX activity by complementation of the Escherischia coli strain SAS38X which lacks PPOX activity. Ten mutants (G40E, L85P, G232R, de1281H, V282D, L295P, V335G, S350P, L444P, G453V) had no detectable PPOX activity. PPOX activity of the remaining 12 mutants (L15F, R38P, L73P, V84G, D143V, R152C, L154P, V158M, R168H, A172V, V290L, G453R) ranged from less than 1% to 9.2% of wild-type activity. Our findings show that all 22 mutations substantially impair or abolish PPOX activity in a prokaryotic expression system and add to the evidence that they cause VP.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Functional studies of mutations in the human protoporphyrinogen oxidase gene in variegate porphyria. 1192 51

Variegate porphyria (VP) is caused by the founder-type protoporphyrinogen oxidase (PPOX) gene mutation R59W in the majority of South African patients. VP is inherited as an autosomal dominant disease with incomplete penetrance and no genotype-phenotype association has been established to date. In an attempt to determine whether a relatively common mutation in the promoter region of the gene (-1081G>A) represents a low-expression allele that may influence clinical manifestation of the disease when inherited from the non-carrier (R59W-negative) parent, we have studied the effect of the mutated allele using an in vitro luciferase assay. Haplotype analysis was furthermore used to evaluate the added information obtained by considering the possible influence of this mutation in combination with a polymorphism in intron 2 (206G>C) of the gene in a genotype-phenotype correlation study. Although the mutation at nucleotide -1081 resulted in a significant reduction in transcriptional activity relative to the reference wild type, no evidence could be obtained that a specific haplotype inherited from the normal parent affects clinical expression of the disease. We thus conclude that other factors such as modifier loci unrelated to the PPOX gene may determine clinical manifestation of VP.
Cell Mol Biol (Noisy-le-grand) 2002 Feb
PMID:Haplotype analysis excludes the functional protoporphyrinogen oxidase promoter polymorphism -1081G>A as a modifying factor in the clinical expression of variegate porphyria. 1193 Sep 46

The porphyrias are disorders associated with inherited or acquired enzyme deficiencies in the heme biosynthetic pathway. The differential diagnosis is often difficult since the phenotype is very similar in some forms and the biochemical tests are not commonly available. Here we provide an update on the molecular diagnosis of porphyrias in Italy and a flow-chart to facilitate the identification of mutations in heme biosynthetic genes. The molecular analysis has allowed us to identify the molecular defect underlying the disease in 66 probands with different porphyrias [acute intermittent porphyria (AIP), variegate porphyria (VP), porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP)]. No Italian patients with defects in coproporphyrinogen oxidise (CPOX) gene, responsible for hereditary coproporphyria (HCP), have been detected. The molecular characterization has been extended to 115 relatives with the identification of 55 asymptomatic mutation carriers and 60 normal subjects. We have so far identified 50 different mutations among 4 genes associated with the most common porphyrias showing a high molecular heterogeneity: 22 in the hydroxymethylbilane synthase (HMBS) gene (AIP), 7 in the protoporphyrinogen oxidase (PPOX) gene (VP), 16 in the uroporphyrinogen decarboxylase (UROD) gene (PCT) and 5 in the ferrochelatase (FECH) gene (EPP). Among the 50 molecular defects, 29 seem to be restricted to the Italian population.
Cell Mol Biol (Noisy-le-grand) 2002 Dec
PMID:Molecular characterization of porphyrias in Italy: a diagnostic flow-chart. 1269 45

The porphyrias are a group of inherited metabolic disorders of heme biosynthesis which result from a partial deficiency in one of its seven specific enzymes, after its first and rate limiting enzyme, delta-aminolevulinic acid synthetase. They can be classified on the basis of their clinical manifestations into cutaneous, acute and mixed disorders. Acute intermittent porphyria (AIP) is the most common type of hepatic acute porphyrias, inherited as an autosomal dominant trait, caused by a defect in the gene which codifies for the heme enzyme porphobilinogen deaminase. Its prevalence in the Argentinean population is about 1:125,000. A partial deficiency in another enzyme, protoporphyrinogen oxidase, produces variegate porphyria (VP), the second acute porphyria most frequent in the Argentinean population (1:600,000). Here, we review all the mutations we have found in 46 AIP and 9 VP unrelated Argentinean patients. To screen for mutations in symptomatic patients, we have proposed a geneticresearch strategy.
Cell Mol Biol (Noisy-le-grand) 2003 Jun
PMID:Acute porphyrias in the Argentinean population: a review. 1289 39


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