The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Bernard Grandchamp - One of the best experts on this subject based on the ideXlab platform.
-
Review: molecular pathogenesis of hepatic acute porphyrias.
Journal of Gastroenterology and Hepatology, 1996Co-Authors: Bernard Grandchamp, Jerome Lamoril, Jean-charles Deybach, Yves 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.
-
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.
-
a molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria a variant form of Hereditary Coproporphyria
Human Molecular Genetics, 1995Co-Authors: Jerome Lamoril, Vasco Da Silva, Jean-charles Deybach, Bernard Grandchamp, Pavel Martásek, Yves 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
-
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 Martásek, 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.
-
homozygous Hereditary Coproporphyria caused by an arginine to tryptophane substitution in coproporphyrinogen oxidase and common intragenic polymorphisms
Human Molecular Genetics, 1994Co-Authors: Pavel Martásek, Yves 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
Yves Nordmann - One of the best experts on this subject based on the ideXlab platform.
-
A molecular, enzymatic and clinical study in a family with Hereditary Coproporphyria
Journal of Inherited Metabolic Disease, 2002Co-Authors: Udo Groß, U Meissauer, Mirko Doss, Jerome Lamoril, Jean-charles Deybach, Yves NordmannAbstract: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.
-
molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with Hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: Udo Groß, U Meissauer, Alexandra Kühnel, Jean-charles Deybach, Yves Nordmann, Pavel Martásek, 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.
-
Human Hereditary hepatic porphyrias.
Clinica Chimica Acta, 2002Co-Authors: Yves Nordmann, Hervé PuyAbstract:The human Hereditary hepatic porphyrias are diseases due to marked deficiencies of enzymes in the heme biosynthetic pathway. Porphyrias can be classified as either hepatic or erythroid, depending on the major production site of porphyrins or their precursors. The pathogenesis of inherited hepatic porphyrias has now been defined at the molecular level. Some gene carriers are vulnerable to a range of exogenous and endogenous factors, which may trigger neuropsychiatric and/or cutaneous symptoms. Early diagnosis is of prime importance since it makes way for counselling. In this article we present an overview of recent advances on hepatic porphyrias: 5-aminolevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria (AIP), porphyria cutanea tarda (PCT), Hereditary Coproporphyria (HC), and variegate porphyria (VP).
-
occurrence of hepatocellular carcinoma in a case of Hereditary Coproporphyria
The American Journal of Gastroenterology, 1997Co-Authors: Christophe Andant, Jean-charles Deybach, Jean Claude Soule, Yves 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.
-
Review: molecular pathogenesis of hepatic acute porphyrias.
Journal of Gastroenterology and Hepatology, 1996Co-Authors: Bernard Grandchamp, Jerome Lamoril, Jean-charles Deybach, Yves 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.
Pavel Martásek - One of the best experts on this subject based on the ideXlab platform.
-
structural basis of Hereditary Coproporphyria
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Eva Flachsova, Michaela Bodnarova, Borries Demeler, Pavel Martásek, 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.
-
molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with Hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: Udo Groß, U Meissauer, Alexandra Kühnel, Jean-charles Deybach, Yves Nordmann, Pavel Martásek, 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.
-
systematic analysis of coproporphyrinogen oxidase gene defects in Hereditary Coproporphyria and mutation update
Human Mutation, 1999Co-Authors: R Rosipal, Jerome Lamoril, Pavel Martásek, Laurent Gouya, Y. Nordmann, V Da Silva, F W M De Rooij, Te K Velde, Jean-charles DeybachAbstract:Hereditary Coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase (CPO). Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often precipitated by drugs, fasting, cyclical hormonal changes, or infectious diseases. Skin photosensitivity may also be present. The seven exons, the exon/intron boundaries and part of 3′ noncoding sequence of the CPO gene were systematically analyzed by an exon-by-exon denaturing gradient gel electrophoresis (DGGE) strategy followed by direct sequencing in seven unrelated heterozygous HC patients from France, Holland, and Czech Republic. Seven novel mutations and two new polymorphisms were detected. Among these mutations: two are missense (G197W, W427R), two are nonsense (Q306X, Q385X), two are small deletions (662del4bp; 1168del3bp removing a glycine at position 390), and one is a splicing mutation (IVS1–15cg) which creates a new acceptor splice site. The pathological significance of the point mutations G197W, W427R, and the in-frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site-directed mutagenesis. These mutations resulted in the absence or a dramatic decrease of CPO activity. The two polymorphisms were localized in noncoding part of the gene: 1) a C/G polymorphism in the promotor region, 142 bp upstream from the transcriptional initiation site (–142C/G), and 2) a 6 bp deletion polymorphism in the 3′ noncoding part of the CPO gene, 574 bp downstream of the last base of the normal termination codon (+574 delATTCTT). Five intragenic dimorphisms are now well characterized and the high degree of allelic heterogeneity in HC is demonstrated with seven new different mutations making a total of nineteen CPO gene defects reported so far. Hum Mutat 13:44–53, 1999. © 1999 Wiley-Liss, Inc.
-
a molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria a variant form of Hereditary Coproporphyria
Human Molecular Genetics, 1995Co-Authors: Jerome Lamoril, Vasco Da Silva, Jean-charles Deybach, Bernard Grandchamp, Pavel Martásek, Yves 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
-
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 Martásek, 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.
Jerome Lamoril - One of the best experts on this subject based on the ideXlab platform.
-
mutations in human cpo gene predict clinical expression of either hepatic Hereditary Coproporphyria or erythropoietic harderoporphyria
Human Molecular Genetics, 2005Co-Authors: Caroline Schmitt, Eva Malonova, Jerome Lamoril, Magali Flamme, Said Lyoumi, Vasco Da Silva, Jean-michel Camadro, Christian Rose, Laurent Gouya, Catherine BoileauAbstract:Hereditary Coproporphyria (HCP), an autosomal dominant acute hepatic porphyria, results from mutations in the gene that encodes coproporphyrinogen III oxidase (CPO). HCP (heterozygous or rarely homozygous) patients present with an acute neurovisceral crisis, sometimes associated with skin lesions. Four patients (two families) have been reported with a clinically distinct variant form of HCP. In such patients, the presence of a specific mutation (K404E) on both alleles or associated with a null allele, produces a unifying syndrome in which hematological disorders predominate: 'harderoporphyria'. Here, we report the fifth case (from a third family) with harderoporphyria. In addition, we show that harderoporphyric patients exhibit iron overload secondary to dyserythropoiesis. To investigate the molecular basis of this peculiar phenotype, we first studied the secondary structure of the human CPO by a predictive method, the hydrophobic cluster analysis (HCA) which allowed us to focus on a region of the enzyme. We then expressed mutant enzymes for each amino acid of the region of interest, as well as all missense mutations reported so far in HCP patients and evaluated the amount of harderoporphyrin in each mutant. Our results strongly suggest that only a few missense mutations, restricted to five amino acids encoded by exon 6, may accumulate significant amounts of harderoporphyrin: D400-K404. Moreover, all other type of mutations or missense mutations mapped elsewhere throughout the CPO gene, lead to coproporphyrin accumulation and subsequently typical HCP. Our findings, reinforced by recent crystallographic results of yeast CPO, shed new light on the genetic predisposition to HCP. It represents a first monogenic metabolic disorder where clinical expression of overt disease is dependent upon the location and type of mutation, resulting either in acute hepatic or in erythropoietic porphyria.
-
A molecular, enzymatic and clinical study in a family with Hereditary Coproporphyria
Journal of Inherited Metabolic Disease, 2002Co-Authors: Udo Groß, U Meissauer, Mirko Doss, Jerome Lamoril, Jean-charles Deybach, Yves NordmannAbstract: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.
-
Characterization of Mutations in the CPO Gene in British Patients Demonstrates Absence of Genotype-Phenotype Correlation and Identifies Relationship between Hereditary Coproporphyria and Harderoporphyria
American Journal of Human Genetics, 2001Co-Authors: Jerome Lamoril, Jacqueline R. Woolf, Sharon D Whatley, Vasco Da Silva, Jean-charles Deybach, Caroline Martin, George H. ElderAbstract:Hereditary Coproporphyria (HCP) is the least common of the autosomal dominant acute hepatic porphyrias. It results from mutations in the CPO gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. A few patients have also been reported who are homoallellic or heteroallelic for CPO mutations and are clinically distinct from those with HCP. In such patients the presence of a specific mutation (K404E) on one or both alleles produces a neonatal hemolytic anemia that is known as “harderoporphyria”; mutations on both alleles elsewhere in the gene give rise to the “homozygous” variant of HCP. The molecular relationship between these disorders and HCP has not been defined. We describe the molecular investigation and clinical features of 17 unrelated British patients with HCP. Ten novel and four previously reported CPO mutations, together with three previously unrecognized single-nucleotide polymorphisms, were identified in 15 of the 17 patients. HCP is more heterogeneous than other acute porphyrias, with all but one mutation being restricted to a single family, with a predominance of missense mutations (10 missense, 2 nonsense, 1 frameshift, and 1 splice site). Of the four known mutations, one (R331W) has previously been reported to cause disease only in homozygotes. Heterologous expression of another mutation (R401W) demonstrated functional properties similar to those of the K404E harderoporphyria mutation. In all patients, clinical presentation was uniform, in spite of the wide range (1%–64%) of residual coproporphyrinogen oxidase activity, as determined by heterologous expression. Our findings add substantially to knowledge of the molecular epidemiology of HCP, show that single copies of CPO mutations that are known or predicted to cause “homozygous” HCP or harderoporphyria can produce typical HCP in adults, and demonstrate that the severity of the phenotype does not correlate with the degree of inactivation by mutation of coproporphyrinogen oxidase.
-
compound heterozygous Hereditary Coproporphyria with fluorescing teeth
Annals of Clinical Biochemistry, 1999Co-Authors: M Doss, Jerome Lamoril, Jean-charles Deybach, Karl Jacob, U Gross, Ch Kranl, M O Doss, Y Da Silva, A G Freesemann, N SeppAbstract:M 0 Doss', U Gross', J Lamoril-, Ch KranP, K Jacob", M Doss', V da Silva-, A G Freesemann', J-Ch Deybach-, N Sepp! and Y Nordmann? From the I Division of Clinical Biochemistry, Philipps University Hospital, Deutschhausstrasse 17~ , 35037 Marburg, Germany, the 2Department ofBiochemistry, Hdpital Louis Mourier, Colombes, France, the 3University Hospital for Dermatology and Venereology, Innsbruck, Austria, and the "Institute of Clinical Chemistry, University Hospital Grosshadern, Munich, Germany
-
systematic analysis of coproporphyrinogen oxidase gene defects in Hereditary Coproporphyria and mutation update
Human Mutation, 1999Co-Authors: R Rosipal, Jerome Lamoril, Pavel Martásek, Laurent Gouya, Y. Nordmann, V Da Silva, F W M De Rooij, Te K Velde, Jean-charles DeybachAbstract:Hereditary Coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase (CPO). Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often precipitated by drugs, fasting, cyclical hormonal changes, or infectious diseases. Skin photosensitivity may also be present. The seven exons, the exon/intron boundaries and part of 3′ noncoding sequence of the CPO gene were systematically analyzed by an exon-by-exon denaturing gradient gel electrophoresis (DGGE) strategy followed by direct sequencing in seven unrelated heterozygous HC patients from France, Holland, and Czech Republic. Seven novel mutations and two new polymorphisms were detected. Among these mutations: two are missense (G197W, W427R), two are nonsense (Q306X, Q385X), two are small deletions (662del4bp; 1168del3bp removing a glycine at position 390), and one is a splicing mutation (IVS1–15cg) which creates a new acceptor splice site. The pathological significance of the point mutations G197W, W427R, and the in-frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site-directed mutagenesis. These mutations resulted in the absence or a dramatic decrease of CPO activity. The two polymorphisms were localized in noncoding part of the gene: 1) a C/G polymorphism in the promotor region, 142 bp upstream from the transcriptional initiation site (–142C/G), and 2) a 6 bp deletion polymorphism in the 3′ noncoding part of the CPO gene, 574 bp downstream of the last base of the normal termination codon (+574 delATTCTT). Five intragenic dimorphisms are now well characterized and the high degree of allelic heterogeneity in HC is demonstrated with seven new different mutations making a total of nineteen CPO gene defects reported so far. Hum Mutat 13:44–53, 1999. © 1999 Wiley-Liss, Inc.
Jean-charles Deybach - One of the best experts on this subject based on the ideXlab platform.
-
A molecular, enzymatic and clinical study in a family with Hereditary Coproporphyria
Journal of Inherited Metabolic Disease, 2002Co-Authors: Udo Groß, U Meissauer, Mirko Doss, Jerome Lamoril, Jean-charles Deybach, Yves NordmannAbstract: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.
-
molecular immunological enzymatic and biochemical studies of coproporphyrinogen oxidase deficiency in a family with Hereditary Coproporphyria
Cellular and Molecular Biology, 2002Co-Authors: Udo Groß, U Meissauer, Alexandra Kühnel, Jean-charles Deybach, Yves Nordmann, Pavel Martásek, 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.
-
Characterization of Mutations in the CPO Gene in British Patients Demonstrates Absence of Genotype-Phenotype Correlation and Identifies Relationship between Hereditary Coproporphyria and Harderoporphyria
American Journal of Human Genetics, 2001Co-Authors: Jerome Lamoril, Jacqueline R. Woolf, Sharon D Whatley, Vasco Da Silva, Jean-charles Deybach, Caroline Martin, George H. ElderAbstract:Hereditary Coproporphyria (HCP) is the least common of the autosomal dominant acute hepatic porphyrias. It results from mutations in the CPO gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. A few patients have also been reported who are homoallellic or heteroallelic for CPO mutations and are clinically distinct from those with HCP. In such patients the presence of a specific mutation (K404E) on one or both alleles produces a neonatal hemolytic anemia that is known as “harderoporphyria”; mutations on both alleles elsewhere in the gene give rise to the “homozygous” variant of HCP. The molecular relationship between these disorders and HCP has not been defined. We describe the molecular investigation and clinical features of 17 unrelated British patients with HCP. Ten novel and four previously reported CPO mutations, together with three previously unrecognized single-nucleotide polymorphisms, were identified in 15 of the 17 patients. HCP is more heterogeneous than other acute porphyrias, with all but one mutation being restricted to a single family, with a predominance of missense mutations (10 missense, 2 nonsense, 1 frameshift, and 1 splice site). Of the four known mutations, one (R331W) has previously been reported to cause disease only in homozygotes. Heterologous expression of another mutation (R401W) demonstrated functional properties similar to those of the K404E harderoporphyria mutation. In all patients, clinical presentation was uniform, in spite of the wide range (1%–64%) of residual coproporphyrinogen oxidase activity, as determined by heterologous expression. Our findings add substantially to knowledge of the molecular epidemiology of HCP, show that single copies of CPO mutations that are known or predicted to cause “homozygous” HCP or harderoporphyria can produce typical HCP in adults, and demonstrate that the severity of the phenotype does not correlate with the degree of inactivation by mutation of coproporphyrinogen oxidase.
-
compound heterozygous Hereditary Coproporphyria with fluorescing teeth
Annals of Clinical Biochemistry, 1999Co-Authors: M Doss, Jerome Lamoril, Jean-charles Deybach, Karl Jacob, U Gross, Ch Kranl, M O Doss, Y Da Silva, A G Freesemann, N SeppAbstract:M 0 Doss', U Gross', J Lamoril-, Ch KranP, K Jacob", M Doss', V da Silva-, A G Freesemann', J-Ch Deybach-, N Sepp! and Y Nordmann? From the I Division of Clinical Biochemistry, Philipps University Hospital, Deutschhausstrasse 17~ , 35037 Marburg, Germany, the 2Department ofBiochemistry, Hdpital Louis Mourier, Colombes, France, the 3University Hospital for Dermatology and Venereology, Innsbruck, Austria, and the "Institute of Clinical Chemistry, University Hospital Grosshadern, Munich, Germany
-
systematic analysis of coproporphyrinogen oxidase gene defects in Hereditary Coproporphyria and mutation update
Human Mutation, 1999Co-Authors: R Rosipal, Jerome Lamoril, Pavel Martásek, Laurent Gouya, Y. Nordmann, V Da Silva, F W M De Rooij, Te K Velde, Jean-charles DeybachAbstract:Hereditary Coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase (CPO). Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often precipitated by drugs, fasting, cyclical hormonal changes, or infectious diseases. Skin photosensitivity may also be present. The seven exons, the exon/intron boundaries and part of 3′ noncoding sequence of the CPO gene were systematically analyzed by an exon-by-exon denaturing gradient gel electrophoresis (DGGE) strategy followed by direct sequencing in seven unrelated heterozygous HC patients from France, Holland, and Czech Republic. Seven novel mutations and two new polymorphisms were detected. Among these mutations: two are missense (G197W, W427R), two are nonsense (Q306X, Q385X), two are small deletions (662del4bp; 1168del3bp removing a glycine at position 390), and one is a splicing mutation (IVS1–15cg) which creates a new acceptor splice site. The pathological significance of the point mutations G197W, W427R, and the in-frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site-directed mutagenesis. These mutations resulted in the absence or a dramatic decrease of CPO activity. The two polymorphisms were localized in noncoding part of the gene: 1) a C/G polymorphism in the promotor region, 142 bp upstream from the transcriptional initiation site (–142C/G), and 2) a 6 bp deletion polymorphism in the 3′ noncoding part of the CPO gene, 574 bp downstream of the last base of the normal termination codon (+574 delATTCTT). Five intragenic dimorphisms are now well characterized and the high degree of allelic heterogeneity in HC is demonstrated with seven new different mutations making a total of nineteen CPO gene defects reported so far. Hum Mutat 13:44–53, 1999. © 1999 Wiley-Liss, Inc.