Activities of delta-aminolevulinic acid synthetase in the liver and bone marrow of hepatic coproporphyria (hereditary coproporphyria).
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Adult↗
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Results for “Coproporphyria, Hereditary”
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[9 cases of hepatic coproporphyria (hereditary coproporphyria)].
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Acute Disease↗
Structural basis of hereditary coproporphyria.
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 beta-sheet sandwiched by alpha-helices. In the biologically active dimer (K(D) = 5 x 10(-7) M), one monomer rotates relative to the second by approximately 40 degrees 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 beta-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.
Amino Acid Sequence↗
Hereditary coproporphyria.
Hereditary coproporphyria is a rarely diagnosed disease and is one of the acute porphyrias. The classic mental, neurological and abdominal symptoms are often observed, but there appear to be atypical clinical features and laboratory findings that may lead to underdiagnosis. In an oral stomatology practice, a group of patients having oral conditions with unknown pathophysiology and multiple systemic complaints were evaluated for porphyrin abnormalities. Blood enzymes, urine and stool porphyrin panels were usually run. A large number of the patients had the clinical symptomatology and porphyrin abnormalities classically found in hereditary coproporphyria.
Adolescent↗
A novel missense mutation in exon 4 of the human coproporphyrinogen oxidase gene in two patients with hereditary coproporphyria.
Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase. To date, four mutations of the gene have been reported. We report here another mutation in two Japanese families with HCP, which was revealed by analysis of polymerase chain reaction (PCR)-amplified DNA fragments of the gene by a direct-sequencing method. A point mutation, G to A, was found in exon 4 of the gene at position 538 of the cDNA from the reported putative translation initiation codon ATG. This mutation results in a glycine to arginine substitution at amino acid 180. Two carriers in the family were successfully diagnosed by detecting the mutation using restriction analysis of the PCR products.
Adult↗
Two novel mutations and coexistence of the 991C>T and the 1339C>T mutation on a single allele in the coproporphyrinogen oxidase gene in Swedish patients with hereditary coproporphyria.
Hereditary coproporphyria (HCP) is an autosomal dominant disorder, resulting from a partial deficiency of the enzyme coproporphyrinogen oxidase (CPO). This enzyme catalyzes the sixth step of the heme biosynthetic pathway, and mutations in the CPO gene have been coupled to HCP. The present study was undertaken to identify disease-producing mutations in the CPOgene in nine Swedish families with HCP. Exon 1 of the CPO gene of the nine probands was analyzed directly by sequencing, and exons 2-7 were screened by denaturating gradient gel electrophoresis, followed by sequencing of exons showing abnormal band pattern. Mutations were detected in five of the nine families. In two of these families, the novel mutations 623C>T (S208F, exon 2) and 982C>T (R328C, exon 5) were identified, respectively. In the affected members of the other three families, the previously reported mutations 991C>T (R331W, exon 5) and 1339C>T (R447C, exon 7) were shown to coexist on one allele. The present study contributes 2 novel mutations to the 34 that have been previously reported to cause HCP. In addition, this is the first report on patients carrying two HCP-coupled mutations on one allele.
Adult↗
Hereditary coproporphyria.
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.
Amino Acid Sequence↗
Characterization and expression of cDNA encoding coproporphyrinogen oxidase from a patient with hereditary coproporphyria.
Hereditary coproporphyria (HCP) is an acute hepatic porphyria with autosomal dominant inheritance, but with a variable degree of clinical expression. Molecular cloning, sequencing and expression of the defective gene for coproporphyrinogen oxidase (CPO) in a patient with HCP were carried out. Enzyme assays revealed that CPO activity in EBV-transformed lymphoblastoid cells from the proband and one of her sisters was approximately 50% of normal. Nucleotide sequence analysis of CPO cDNAs isolated from the proband's cells demonstrated three base substitutions, and three accompanying amino acid substitutions. An A514-->C transition causing a Asn172-->His substitution occurred in one allele, while two other transitions, G265-->A and G580-->A, caused Gly89-->Ser and Val194-->Ile substitutions, respectively, in the other allele. The A514-->C and the G580-->A transitions are known genetic polymorphisms. Transfection of CPO cDNA into Escherichia coli demonstrated that cDNA with the G265-->A transition produced a protein with less than 5% of normal enzyme activity. These findings indicate that the G265-->A transition, involving the highly conserved glycine residue at the 89th position, is responsible for the CPO defect in the patient and accounts for the partial deficiency of CPO activity in this pedigree.
Amino Acid Sequence↗
A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria.
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.
Amino Acid Sequence↗
[Hereditary coproporphyria (Hepatic coproporphyria), Erythropoietic coproporphyria].
Hereditary coproporphyria (Hepatic coproporphyria: HCP); HCP is the rarest and least recognized among hepatic porphyrias and is characterised by an excess of faecal and urinary excretion of coproporphyrin (mainly isomer III). The deficiency is in coproporphyrinogen oxidase. HCP was first described by Berger and Goldberg in 1955 and was considered an asymptomatic biochemical abnormality. It later became evident that HCP could provoke acute attacks similar to those of acute intermittent porphyria (AIP) and variegate porphyria (VP). Such episodes are often provoked by barbiturates, sulphonamides and other drugs, and include automatic symptoms (hypertension, tachycardia, abdominal pain, constipation), central (epileptic seizures, mental disturbances) and peripheral nervous system dysfunction. During acute attacks, urinary ALA (delta-aminole-vulinic acid) and PBG (porphobilinogen) are elevated just as in AIP and VP, however, a marked elevation of faecal COPRO (coproporphyrin) is diagnostic of HCP. Laparoscopic finding of our case showed a map-like appearance of the liver surface with slightly depressed dark-bluish areas and reddish-brown areas. The liver biopsy specimen showed red fluorescence under ultraviolet light. On HE staining, hydropic degeneration of the hepatocytes and many brown granules in the hepatocytes were seen. A part of the granules stained positive for iron. Schmorl's stain showed many needle-shaped crystallines. Erythropoietic coproporphyria (ECP); Heilmeyer and Clotten have described that elevated PROTO (protoporphyrin) and COPRO were found in the RBC of the patient. Topi et al. described two brothers with cutaneous photosensitivity similar to that of erythropoietic protoporphyria, but with elevated RBC PROTO and COPRO III in both. Very little is known about this disease.
Adult↗
Molecular defects of the coproporphyrinogen oxidase gene in hereditary coproporphyria.
Hereditary coproporphyria (HCP) is an acute hepatic porphyria, and is an autosomal dominant disorder but with a variable degree of clinical expression. Molecular cloning, sequencing and expression of the defective gene for coproporphyrinogen oxidase (CPO) in a patient with HCP were carried out. Enzyme assays revealed that CPO activity in EBV-transformed lymphoblastoid cells from the proband and one of her sisters was approximately 50% of normal. Nucleotide sequence analysis of CPO cDNAs isolated from the proband's cells demonstrated 3 base substitutions which accompanied 3 different amino acid substitutions. An A514-->C transition causing an Asn172-->His substitution occurred in one allele, while two other transitions, G265-->A and G580-->A, caused Gly89-->Ser and Val194-->Ile substitutions, respectively, in the other allele. The A514-->C and the G580-->A transitions were shown to be genetic polymorphisms. Transfection of CPO cDNA into E. coli demonstrated that cDNA with the G265-->A transition produced a protein with less than 5% of normal enzyme activity. These findings indicate that the G265-->A transition, involving the highly conserved glycine residue at the 89th position, is responsible for the CPO defect in the patient and accounts for the partial deficiency of CPO activity in this pedigree. This mutation is different from three other mutations reported in patients with HCP. Molecular defects in the porphyrias including HCP are highly heterogeneous.
Cell Line, Transformed↗
Uneventful propofol anesthesia in a patient with coexisting hereditary coproporphyria and hereditary angioneurotic edema.
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Adult↗
Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family.
Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase (CPO) caused by a mutation in the CPO gene. Only 11 mutations of the gene have been reported in HCP patients. We report another mutation in a Japanese family. Polymerase chain reaction-single strand conformational polymorphism and direct sequence analyses demonstrated a C to T substitution in exon 1 of the CPO gene at nucleotide position 85, which lies in the putative presequence for targeting to mitochondria. This mutation changes the codon for glutamine to a termination codon at amino acid position 29. MaeI restriction analysis showed two other carriers in the family. The C-T mutation is located within a recently proposed putative alternative translation initiation codon (TIC-1), supporting that TIC-1 is the real TIC rather than TIC-2.
Adult↗
Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria.
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.
Amino Acid Sequence↗
Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria.
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.
Amino Acid Sequence↗
[Hereditary coproporphyria. 7 cases].
Hereditary coprophyria, known since 1955, is a rare variety of hepatic porphyria. The clinical picture is similar to that of acute intermittent porphyria with certain minor differences; neurological manifestations being rarer in particular. The essential biological characteristic is the massive excretion, in the urine and faeces, of coproporphyrins whilst the excretion of porphobilinogen and delta-amino-laevulinic acid is only slightly increased. As in acute intermittent porphyria, certain medications have an adverse effect, especially the barbiturates. The exact nature of the biochemical lesion is not understood but its hereditary nature has been demonstrated. 25 families have been reported in the literature up to the present time. The authors report two cases of hereditary coproporphyria with peripheral paralysis and respiratory failure, the outcome being fatal in one case. Study of the families led to the discovery of 3 other cases in the second family and 2 latent forms in the first.
Adolescent↗
Hereditary coproporphyria: an imitator of multiple sclerosis.
Hereditary coproporphyria can cause both peripheral neuropathy and central nervous system abnormalities. There are several similarities between multiple sclerosis and hereditary coproporphyria that are probably due to the central nervous system dysfunction present in both. This report describes a 62-year-old man with a five-year history of progressive paraparesis initially diagnosed as multiple sclerosis. Supporting evidence for the diagnosis of a demyelinating disease included three oligoclonal bands in the patient's cerebral spinal fluid, a prolonged visual evoked response bilaterally, abnormal sensory evoked potentials, and an area of increased signal in the posterior cervical cord suggestive of demyelination that was demonstrated on magnetic resonance imaging (MRI). Features atypical for multiple sclerosis were hypoactive deep-tendon reflexes, electromyographic evidence of peripheral neuropathy, and severe constipation. Elevated urine porphyrins and decreased levels of coproporphyrinogen oxidase confirmed the correct diagnosis of hereditary coproporphyria. The patient improved after being placed on a high-carbohydrate diet. Although central demyelination is known to occur in patients with porphyria, delayed evoked potentials and MRI abnormalities have not been previously reported.
Diagnosis, Differential↗
Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update.
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 (662de14bp; 1168del3bp removing a glycine at position 390), and one is a splicing mutation (IVS1-15c-->g) 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.
Adult↗