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Y Nordmann - One of the best experts on this subject based on the ideXlab platform.
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A molecular, enzymatic and clinical study in a family with hereditary Coproporphyria
Journal of Inherited Metabolic Disease, 2002Co-Authors: U. Gross, Jerome Lamoril, U Meissauer, Jean-charles Deybach, Y Nordmann, Mirko DossAbstract:A 30-year-old woman suffered from acute crises with abdominal, neurological and psychiatric complaints. Urinary haem precursors and faecal porphyrins were excessively elevated compared to the upper level of the normal range. Urinary coproporphyrin isomer III was increased and faecal copro-porphyrin isomers I and III showed a complete inversion of the normal ratio. Thus, hereditary Coproporphyria was diagnosed in this woman. The father, one brother and a sister were shown to be gene carriers of hereditary copro- porphyria by their urinary and faecal excretory constellations. The excretory patterns of the mother and a second brother were normal. Coproporphyrinogen oxidase activity was decreased to 49% and 58% in the patient and her father, respectively. The mother's enzyme activity was normal (98%). Copro-porphyrinogen oxidase concentration was enhanced 1.8-fold and 2.7-fold in the patient and her father, respectively. Mutation analysis revealed the insertion of an adenine at position 857 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by denaturing gradient gel electrophoresis in the patient and her father. The patient was treated by intravenous interval therapy with haem arginate for 10 months, with good clinical and metabolic response.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: Ulrich Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, K Jacob, Pavel Martasek, Mirko DossAbstract:A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro(1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III= 25-35%). The excretion of porphyrin precursors (δ-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138 ′ 21 pkat/g protein; x ′ s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: U. Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, Pavel Martasek, Karl Jacob, Mirko DossAbstract:: A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro- (1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III = 25-35%). The excretion of porphyrin precursors (delta-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138+/-21 pkat/g protein; x+/-s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
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occurrence of hepatocellular carcinoma in a case of hereditary Coproporphyria
The American Journal of Gastroenterology, 1997Co-Authors: Christophe Andant, Jean-charles Deybach, Jeanclaude Soule, Y NordmannAbstract:: An association between two types of acute hepatic porphyria (porphyria variegata and acute intermittent porphyria) and hepatocellular carcinoma has previously been reported. In these studies, etiological factors for hepatocellular carcinoma were not completely sought. We report here the first case of an association between hepatocellular carcinoma and hereditary Coproporphyria, the third type of acute hepatic porphyria. A 58-yr-old woman with hereditary Coproporphyria presented with a 3.5-cm-diameter hepatocellular carcinoma. Results of exhaustive investigation of etiological factors for hepatocellular carcinoma were negative. Results of microscopic histological analysis of the nontumorous liver were normal. Five years after surgical resection, the patient had no evidence of tumor recurrence.
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Review: molecular pathogenesis of hepatic acute porphyrias.
Journal of Gastroenterology and Hepatology, 1996Co-Authors: Bernard Grandchamp, Jerome Lamoril, Jean-charles Deybach, Y NordmannAbstract:The molecular cloning of cDNA and genes encoding enzymes of the haem biosynthetic pathway have permitted the genetic defects underlying acute intermittent porphyria (AIP) and hereditary Coproporphyria to be unravelled. In AIP, many different gene abnormalities have been documented since 1989. The prevalence of specific defective alleles among AIP families depends on which human population is studied. Founder effects are likely to account for a high frequency of a single mutation in Finland and, to a lesser extent, in Holland, while many other mutations have only been found once, each of them in a single family. In hereditary Coproporphyria several different mutations have already been identified since 1994, suggesting that a large allelic heterogeneity also exists. The search for mutations in variegate porphyria has just started since the recent publication of the human cDNA sequence. Direct detection of the mutations using DNA analysis brings a growing contribution to the detection of asymptomatic carriers among relatives of porphyric patients and will, therefore, improve the prevention of acute attacks.
Bernard Grandchamp - One of the best experts on this subject based on the ideXlab platform.
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Review: molecular pathogenesis of hepatic acute porphyrias.
Journal of Gastroenterology and Hepatology, 1996Co-Authors: Bernard Grandchamp, Jerome Lamoril, Jean-charles Deybach, Y NordmannAbstract:The molecular cloning of cDNA and genes encoding enzymes of the haem biosynthetic pathway have permitted the genetic defects underlying acute intermittent porphyria (AIP) and hereditary Coproporphyria to be unravelled. In AIP, many different gene abnormalities have been documented since 1989. The prevalence of specific defective alleles among AIP families depends on which human population is studied. Founder effects are likely to account for a high frequency of a single mutation in Finland and, to a lesser extent, in Holland, while many other mutations have only been found once, each of them in a single family. In hereditary Coproporphyria several different mutations have already been identified since 1994, suggesting that a large allelic heterogeneity also exists. The search for mutations in variegate porphyria has just started since the recent publication of the human cDNA sequence. Direct detection of the mutations using DNA analysis brings a growing contribution to the detection of asymptomatic carriers among relatives of porphyric patients and will, therefore, improve the prevention of acute attacks.
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Molecular abnormalities of coproporphyrinogen oxidase in patients with hereditary Coproporphyria
Journal of Bioenergetics and Biomembranes, 1995Co-Authors: Bernard Grandchamp, Jerome LamorilAbstract:Genetic defects of coproporphyrinogen oxidase (CPO) lead to hereditary Coproporphyria, an inherited autosomal dominant porphyria. The recent cloning of human cDNAs and of the gene encoding CPO permits deducing the primary structure of the CPO protein and elucidating the molecular basis of HC in some families.
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a molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria a variant form of hereditary Coproporphyria
Human Molecular Genetics, 1995Co-Authors: J Lamoril, Bernard Grandchamp, Jean-charles Deybach, Pavel Martasek, Vasco Da Silva, Y NordmannAbstract:Hereditary Coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by a deficient activity of coproporphyrinogen IX oxidase (CPX). We previously described harderoporphyria, a homozygous variant form of Coproporphyria in three siblings, characterized by a massive excretion of harderoporphyrin and a marked decrease of coproporphyrinogen IX oxidase activity. In this kindred, the transmission of the disease was autosomal recessive. In the present study, sequencing of cDNA and genomic DNA from these patients revealed a point mutation resulting in a lysine to glutamic acid substitution (K304E) in exon 6 of the gene and the absence of the normal allele, suggesting a homozygous state for the mutation. Expression studies of normal and mutated cDNAs in E.coli demonstrated that this amino acid substitution was responsible for the important decrease in the enzyme activity and for the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal suggesting that the lysine at position 304 is important for binding the substrate: a slightly increased sensitivity to thermal denaturation was also observed
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localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12
Human Genetics, 1994Co-Authors: Valère Cacheux, Marie Helene Delfau, Luc Druart, Francoise Fougerousse, Gérard Tachdjian, Pavel Martasek, Bernard GrandchampAbstract:The human gene encoding coproporphyrinogen oxidase is the defective gene in hereditary Coproporphyria. This gene was mapped to chromosome band 3q12 using fluorescent in situ hybridization. The chromosomal localization was confirmed by cosegregation of the human gene with chromosome 3 in a panel of human/rodent somatic hybrids.
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homozygous hereditary Coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms
Human Molecular Genetics, 1994Co-Authors: Pavel Martasek, Y Nordmann, Bernard GrandchampAbstract:Coproporphyrinogen oxidase is a mitochondrial hemebiosynthetic enzyme that converts coproporphyrinogen to protoporphyrinogen. Inherited deficiency of this enzyme causes the human genetic disease hereditary Coproporphyria. Recently, we isolated, sequenced and expressed the cDNA encoding human coproporphyrinogen oxidase. This allowed us to investigate the nature of the defect leading to a profound deficiency of coproporphyrinogen oxidase in a patient with homozygous hereditary Coproporphyria. Using reversetranscription, amplification of the cDNA and direct sequencing of the amplified products, we found a point mutation resulted in an arginine to tryptophane substitution (R231W). Expression studies of normal and mutated cDNAs in a bacterial system demonstrated that this substitution resulted in the synthesis of an unstable protein with a residual catalytic activity
Pavel Martasek - One of the best experts on this subject based on the ideXlab platform.
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structural basis of hereditary Coproporphyria
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Eva Flachsova, Pavel Martasek, Michaela Bodnarova, Borries Demeler, C S RamanAbstract:Hereditary Coproporphyria is an autosomal dominant disorder resulting from the half-normal activity of coproporphyrinogen oxidase (CPO), a mitochondrial enzyme catalyzing the antepenultimate step in heme biosynthesis. The mechanism by which CPO catalyzes oxidative decarboxylation, in an extraordinary metal- and cofactor-independent manner, is poorly understood. Here, we report the crystal structure of human CPO at 1.58-A resolution. The structure reveals a previously uncharacterized tertiary topology comprising an unusually flat seven-stranded β-sheet sandwiched by α-helices. In the biologically active dimer (KD = 5 × 10-7 M), one monomer rotates relative to the second by ≈40° to create an intersubunit interface in close proximity to two independent enzymatic sites. The unexpected finding of citrate at the active site allows us to assign Ser-244, His-258, Asn-260, Arg-262, Asp-282, and Arg-332 as residues mediating substrate recognition and decarboxylation. We favor a mechanism in which oxygen serves as the immediate electron acceptor, and a substrate radical or a carbanion with substantial radical character participates in catalysis. Although several mutations in the CPO gene have been described, the molecular basis for how these alterations diminish enzyme activity is unknown. We show that deletion of residues (392-418) encoded by exon six disrupts dimerization. Conversely, harderoporphyria-causing K404E mutation precludes a type I β-turn from retaining the substrate for the second decarboxylation cycle. Together, these findings resolve several questions regarding CPO catalysis and provide insights into hereditary Coproporphyria.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: Ulrich Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, K Jacob, Pavel Martasek, Mirko DossAbstract:A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro(1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III= 25-35%). The excretion of porphyrin precursors (δ-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138 ′ 21 pkat/g protein; x ′ s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: U. Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, Pavel Martasek, Karl Jacob, Mirko DossAbstract:: A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro- (1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III = 25-35%). The excretion of porphyrin precursors (delta-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138+/-21 pkat/g protein; x+/-s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
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Hereditary Coproporphyria.
Seminars in liver disease, 1998Co-Authors: Pavel MartasekAbstract:Hereditary Coproporphyria (HC) is a rare acute hepatic porphyria. Attacks may be precipitated by certain drugs, alcohol, infections, or low caloric intake. HC is caused by defects in the enzyme coproporphyrinogen III oxidase (copro-ox) which converts coproporphyrinogen III (coprogen) to protoporphyrinogen IX (protogen). Coprogen is made mainly in the liver and is excreted predominantly in the feces. The dramatic increase in coproporphyrin III (copro) excretion (10-200 times compared with the control value) with intensive red fluorescence under UV light is a specific and easily detectable marker for diagnosis of acute attacks of HC. HC is inherited as an autosomally dominant genetic defect. The cDNA and gene encoding copro-ox have been isolated recently and mutations have been identified, providing critical information concerning molecular heterogeneity and the potential for molecular diagnosis. In this review, we describe 10 mutations in the copro-ox gene which are spread along six exons. It is postulated that DNA analysis of gene carriers and the use of heme arginate for specific treatment will improve the care of HC patients dramatically.
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a molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria a variant form of hereditary Coproporphyria
Human Molecular Genetics, 1995Co-Authors: J Lamoril, Bernard Grandchamp, Jean-charles Deybach, Pavel Martasek, Vasco Da Silva, Y NordmannAbstract:Hereditary Coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by a deficient activity of coproporphyrinogen IX oxidase (CPX). We previously described harderoporphyria, a homozygous variant form of Coproporphyria in three siblings, characterized by a massive excretion of harderoporphyrin and a marked decrease of coproporphyrinogen IX oxidase activity. In this kindred, the transmission of the disease was autosomal recessive. In the present study, sequencing of cDNA and genomic DNA from these patients revealed a point mutation resulting in a lysine to glutamic acid substitution (K304E) in exon 6 of the gene and the absence of the normal allele, suggesting a homozygous state for the mutation. Expression studies of normal and mutated cDNAs in E.coli demonstrated that this amino acid substitution was responsible for the important decrease in the enzyme activity and for the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal suggesting that the lysine at position 304 is important for binding the substrate: a slightly increased sensitivity to thermal denaturation was also observed
Mirko Doss - One of the best experts on this subject based on the ideXlab platform.
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A molecular, enzymatic and clinical study in a family with hereditary Coproporphyria
Journal of Inherited Metabolic Disease, 2002Co-Authors: U. Gross, Jerome Lamoril, U Meissauer, Jean-charles Deybach, Y Nordmann, Mirko DossAbstract:A 30-year-old woman suffered from acute crises with abdominal, neurological and psychiatric complaints. Urinary haem precursors and faecal porphyrins were excessively elevated compared to the upper level of the normal range. Urinary coproporphyrin isomer III was increased and faecal copro-porphyrin isomers I and III showed a complete inversion of the normal ratio. Thus, hereditary Coproporphyria was diagnosed in this woman. The father, one brother and a sister were shown to be gene carriers of hereditary copro- porphyria by their urinary and faecal excretory constellations. The excretory patterns of the mother and a second brother were normal. Coproporphyrinogen oxidase activity was decreased to 49% and 58% in the patient and her father, respectively. The mother's enzyme activity was normal (98%). Copro-porphyrinogen oxidase concentration was enhanced 1.8-fold and 2.7-fold in the patient and her father, respectively. Mutation analysis revealed the insertion of an adenine at position 857 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by denaturing gradient gel electrophoresis in the patient and her father. The patient was treated by intravenous interval therapy with haem arginate for 10 months, with good clinical and metabolic response.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: Ulrich Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, K Jacob, Pavel Martasek, Mirko DossAbstract:A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro(1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III= 25-35%). The excretion of porphyrin precursors (δ-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138 ′ 21 pkat/g protein; x ′ s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: U. Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, Pavel Martasek, Karl Jacob, Mirko DossAbstract:: A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro- (1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III = 25-35%). The excretion of porphyrin precursors (delta-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138+/-21 pkat/g protein; x+/-s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
Jean-charles Deybach - One of the best experts on this subject based on the ideXlab platform.
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A molecular, enzymatic and clinical study in a family with hereditary Coproporphyria
Journal of Inherited Metabolic Disease, 2002Co-Authors: U. Gross, Jerome Lamoril, U Meissauer, Jean-charles Deybach, Y Nordmann, Mirko DossAbstract:A 30-year-old woman suffered from acute crises with abdominal, neurological and psychiatric complaints. Urinary haem precursors and faecal porphyrins were excessively elevated compared to the upper level of the normal range. Urinary coproporphyrin isomer III was increased and faecal copro-porphyrin isomers I and III showed a complete inversion of the normal ratio. Thus, hereditary Coproporphyria was diagnosed in this woman. The father, one brother and a sister were shown to be gene carriers of hereditary copro- porphyria by their urinary and faecal excretory constellations. The excretory patterns of the mother and a second brother were normal. Coproporphyrinogen oxidase activity was decreased to 49% and 58% in the patient and her father, respectively. The mother's enzyme activity was normal (98%). Copro-porphyrinogen oxidase concentration was enhanced 1.8-fold and 2.7-fold in the patient and her father, respectively. Mutation analysis revealed the insertion of an adenine at position 857 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by denaturing gradient gel electrophoresis in the patient and her father. The patient was treated by intravenous interval therapy with haem arginate for 10 months, with good clinical and metabolic response.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: Ulrich Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, K Jacob, Pavel Martasek, Mirko DossAbstract:A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro(1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III= 25-35%). The excretion of porphyrin precursors (δ-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138 ′ 21 pkat/g protein; x ′ s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
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molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: U. Gross, U Meissauer, Jean-charles Deybach, Y Nordmann, Alexandra Kühnel, Pavel Martasek, Karl Jacob, Mirko DossAbstract:: A 27-year-old woman who had recurrent pain in renal bed since 1998 with increasing character, was stationary admitted. The patient showed dark urine, complained of hair loss and took since 1994 a hormonal oral contraceptive. No photosensitivity was observed. Determinations of urinary porphyrin metabolites in 1998 revealed a porphyria cutanea tarda like excretion pattern with elevations of uro- (1767 nmol/24 hr, normal <29 nmol/24 hr) and heptacarboxyporphyrin (568 nmol/24 hr; normal <4 nmol/24 hr). Follow-up studies in feces showed the characteristics of a hereditary Coproporphyria with dominance of coproporphyrin isomer III (total= 1470 nmol/g, isomer III= 93%), (normal: <37 nmol/g, isomer III = 25-35%). The excretion of porphyrin precursors (delta-aminolevulinic acid and porphobilinogen) was increased by taking an ethinylestradiol-cyproteronacetate-preparation, but acute and/or chronic manifestations were not observed. Coproporphyrinogen oxidase activity was decreased to 35% in the patient (normal=138+/-21 pkat/g protein; x+/-s), whereas the activity of red cell uroporphyrinogen decarboxylase was normal. Her mother and both sisters could be verified as heterozygous gene carriers of hereditary Coproporphyria by their urinary and fecal excretion parameters and because of reduced coproporphyrinogen oxidase activity up to 50%. The father was normal with respect to his genotype. Molecular analysis revealed a hitherto unknown mutation with the transversion of a cytosine to thymine at nucleotide position 854 in exon 4 of the coproporphyrinogen oxidase gene. The gene defect was confirmed by DGGE in the mother and her three daughters. The investigation of the immunological nature of the defective coproporphyrinogen oxidase gene from the whole family revealed decreased concentrations of coproporphyrinogen oxidase protein in the patient, her mother and her two sisters.
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occurrence of hepatocellular carcinoma in a case of hereditary Coproporphyria
The American Journal of Gastroenterology, 1997Co-Authors: Christophe Andant, Jean-charles Deybach, Jeanclaude Soule, Y NordmannAbstract:: An association between two types of acute hepatic porphyria (porphyria variegata and acute intermittent porphyria) and hepatocellular carcinoma has previously been reported. In these studies, etiological factors for hepatocellular carcinoma were not completely sought. We report here the first case of an association between hepatocellular carcinoma and hereditary Coproporphyria, the third type of acute hepatic porphyria. A 58-yr-old woman with hereditary Coproporphyria presented with a 3.5-cm-diameter hepatocellular carcinoma. Results of exhaustive investigation of etiological factors for hepatocellular carcinoma were negative. Results of microscopic histological analysis of the nontumorous liver were normal. Five years after surgical resection, the patient had no evidence of tumor recurrence.
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Review: molecular pathogenesis of hepatic acute porphyrias.
Journal of Gastroenterology and Hepatology, 1996Co-Authors: Bernard Grandchamp, Jerome Lamoril, Jean-charles Deybach, Y NordmannAbstract:The molecular cloning of cDNA and genes encoding enzymes of the haem biosynthetic pathway have permitted the genetic defects underlying acute intermittent porphyria (AIP) and hereditary Coproporphyria to be unravelled. In AIP, many different gene abnormalities have been documented since 1989. The prevalence of specific defective alleles among AIP families depends on which human population is studied. Founder effects are likely to account for a high frequency of a single mutation in Finland and, to a lesser extent, in Holland, while many other mutations have only been found once, each of them in a single family. In hereditary Coproporphyria several different mutations have already been identified since 1994, suggesting that a large allelic heterogeneity also exists. The search for mutations in variegate porphyria has just started since the recent publication of the human cDNA sequence. Direct detection of the mutations using DNA analysis brings a growing contribution to the detection of asymptomatic carriers among relatives of porphyric patients and will, therefore, improve the prevention of acute attacks.