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Proceedings of the National Academy of... Oct 2005Hereditary coproporphyria is an autosomal dominant disorder resulting from the half-normal activity of coproporphyrinogen oxidase (CPO), a mitochondrial enzyme... (Comparative Study)
Comparative Study
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.
Topics: Amino Acid Sequence; Citric Acid; Coproporphyria, Hereditary; Coproporphyrinogen Oxidase; Crystallography; Dimerization; Humans; Models, Molecular; Molecular Sequence Data; Mutation; Protein Conformation; Sequence Alignment; Ultracentrifugation
PubMed: 16176984
DOI: 10.1073/pnas.0506557102 -
Disease Models & Mechanisms Aug 2017A genome-wide ethyl-N-nitrosourea (ENU) mutagenesis screen in mice was performed to identify novel regulators of erythropoiesis. Here, we describe a mouse line, RBC16,...
A genome-wide ethyl-N-nitrosourea (ENU) mutagenesis screen in mice was performed to identify novel regulators of erythropoiesis. Here, we describe a mouse line, RBC16, which harbours a dominantly inherited mutation in the gene, responsible for production of the haem biosynthesis enzyme, coproporphyrinogen III oxidase (CPOX). A premature stop codon in place of a tryptophan at amino acid 373 results in reduced mRNA expression and diminished protein levels, yielding a microcytic red blood cell phenotype in heterozygous mice. Urinary and faecal porphyrins in female RBC16 heterozygotes were significantly elevated compared with that of wild-type littermates, particularly coproporphyrinogen III, whereas males were biochemically normal. Attempts to induce acute porphyric crises were made using fasting and phenobarbital treatment on females. While fasting had no biochemical effect on RBC16 mice, phenobarbital caused significant elevation of faecal coproporphyrinogen III in heterozygous mice. This is the first known investigation of a mutagenesis mouse model with genetic and biochemical parallels to hereditary coproporphyria.
Topics: Anemia, Hypochromic; Animals; Base Sequence; Biosynthetic Pathways; Coproporphyria, Hereditary; Coproporphyrinogen Oxidase; Disease Models, Animal; Ethylnitrosourea; Fasting; Feces; Female; Heme; Male; Mice, Mutant Strains; Mutagenesis; Mutation; Phenobarbital; Phenotype; Pregnancy
PubMed: 28600349
DOI: 10.1242/dmm.029116 -
Neuropsychopharmacologia Hungarica : a... Mar 2014We report a successful treatment with lamotrigine of a patient with hereditary coproporphyria presenting with affective and psychotic symptoms. (Review)
Review
OBJECTIVE
We report a successful treatment with lamotrigine of a patient with hereditary coproporphyria presenting with affective and psychotic symptoms.
CASE REPORT
M.F., a 38-year-old, single woman was admitted to an acute psychiatric ward because of suddenly emerging psychosis. Ms F's hereditary coproporphyria was diagnosed 9 years before the current admission. While on treatment with olanzapine (20mg/day) the psychotic symptoms have gradually disappeared. In view of her significant mood fluctuations predominantly with depressed phases, lamotrigine was started and titrated up to 125 mg/day. Ms F's mood gradually became euthymic, suicidal ideations and anxiety disappeared. At 5-month follow-up, while still on lamotrigine, her porphyria was asymptomatic.
CONCLUSION
To the best of our knowledge, this is the first report about the safe administration of lamotrigine in hereditary coproporphyria. Lamotrigine did not trigger an acute porphyric attack as confirmed by clinical and laboratory findings.
Topics: Adult; Antipsychotic Agents; Coproporphyria, Hereditary; Depressive Disorder, Major; Female; Humans; Lamotrigine; Psychotic Disorders; Treatment Outcome; Triazines
PubMed: 24687017
DOI: No ID Found -
Journal of Medical Genetics Oct 1984In a family inheriting the hereditary coproporphyria (HCP) gene, where 414 descendants have been traced through six generations and 135 members screened for faecal...
In a family inheriting the hereditary coproporphyria (HCP) gene, where 414 descendants have been traced through six generations and 135 members screened for faecal porphyrins, 27 subjects were found to have inherited the gene as well as the proband. Seven (six female and one male) in retrospect had probably previously suffered from a clinical attack of porphyria. Enzymological studies were carried out on 15 members and two unaffected parents and these results in general agreed with the faecal coproporphyrin readings. Symptomatic illness is low in HCP and is almost always precipitated by drugs known to have an adverse effect on the condition. If the gene is inherited, an attack can occur at any time between puberty and old age, such as in the proband at 84 years. We have detected abnormal faecal coproporphyrin levels in members of this pedigree as young as 12 years and as old as 87 years. Recommendations are given concerning the necessity of tracing relatives who may have inherited the gene and arranging for their biochemical screening and genetic counseling if indicated.
Topics: Adolescent; Adult; Age Factors; Aged; Child; Coproporphyrins; Feces; Female; Genetic Counseling; Humans; Male; Middle Aged; Pedigree; Porphyrias; Porphyrins; Sex Factors
PubMed: 6502649
DOI: 10.1136/jmg.21.5.341 -
Endocrine, Metabolic & Immune Disorders... 2016Hereditary Coproporphyria (HCP) is characterized by abdominal pain, neurologic symptoms and psychiatric disorders, even if it might remain asymptomatic. The...
BACKGROUND
Hereditary Coproporphyria (HCP) is characterized by abdominal pain, neurologic symptoms and psychiatric disorders, even if it might remain asymptomatic. The pathophysiology of both neurologic and psychiatric symptoms is not fully understood. Therefore, aiming to evaluate a possible role of brain blood flow disorders, we have retrospectively investigated cerebral perfusion patterns in Single Photon Emission Computed Tomography (SPECT) studies in HCP patients.
MATERIALS & METHODS
We retrospectively evaluated the medical records of patients diagnosed as being affected by HCP. A total of seven HCP patients had been submitted to brain perfusion SPECT study with 99mTc-Exametazime (hexamethylpropyleneamine oxime, HMPAO) or with its functionally equivalent 99mTc-Bicisate (ECD or Neurolite) according with common procedures. In 3 patients the scintigraphic study had been repeated for a second time after the first evaluation at 3, 10 and 20 months, respectively. All the studied subjects had been also submitted to an electromyographic and a Magnetic Resonance Imaging (MRI) study of the brain.
RESULTS
Mild to moderate perfusion defects were detected in temporal lobes (all 7 patients), frontal lobes (6 patients) and parietal lobes (4 patients). Occipital lobe, basal ganglia and cerebellar involvement were never observed. In the three subjects in which SPECT study was repeated, some recovery of hypo-perfused areas and appearance of new perfusion defects in other brain regions have been found. In all patients electromyography resulted normal and MRI detected few unspecific gliotic lesions only in one patient. Discussion & Conclusions: Since perfusion abnormalities were usually mild to moderate, this can probably explain the normal pattern observed at MRI studies. Compared to MRI, SPECT with 99mTc showed higher sensitivity in HCP patients. Changes observed in HCP patients who had more than one study suggest that transient perfusion defects might be due to a brain artery spasm possibly leading to psychiatric and neurologic symptomatology, as already observed in patients affected by acute intermittent porphyria. This observation, if confirmed by other well designed studies aiming to demonstrate a direct link between artery spasm, perfusion defects and related symptoms could lead to improvements in HCP treatments.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain; Coproporphyria, Hereditary; Female; Humans; Male; Middle Aged; Retrospective Studies; Tomography, Emission-Computed, Single-Photon; Young Adult
PubMed: 26680773
DOI: 10.2174/1871530316666151218151101 -
Molecular Genetics and Metabolism Nov 2019Mouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To... (Review)
Review
Mouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To date, mouse models have been generated for all major porphyrias, with the exception of X-linked protoporphyria (XLP) and the ultra rare 5-aminolevulinic acid dehydratase deficient porphyria (ADP). Mouse models have been generated for the three autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The AIP mice, in particular, provide a useful investigative model as they have been shown to have acute biochemical attacks when induced with the prototypic porphyrinogenic drug, phenobarbital. In addition to providing important insights into the disease pathogenesis of the neurological impairment in AIP, these mice have been valuable for preclinical evaluation of liver-targeted gene therapy and RNAi-mediated approaches. Mice with severe HMBS deficiency, which clinically and biochemically mimic the early-onset homozygous dominant AIP (HD-AIP) patients, have been generated and were used to elucidate the striking phenotypic differences between AIP and HD-AIP. Mice modeling the hepatocutaneous porphyria, porphyria cutanea tarda (PCT), made possible the identification of the iron-dependent inhibitory mechanism of uroporphyrinogen decarboxylase (UROD) that leads to symptomatic PCT. Mouse models for the two autosomal recessive erythropoietic porphyrias, congenital erythropoietic porphyria (CEP) and erythropoeitic protoporphyria (EPP), recapitulate many of the clinical and biochemical features of the severe human diseases and have been particularly useful for evaluation of bone marrow transplantation and hematopoietic stem cell (HSC)-based gene therapy approaches. The EPP mice have also provided valuable insights into the underlying pathogenesis of EPP-induced liver damage and anemia.
Topics: Anemia; Animals; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Genetic Therapy; Humans; Liver; Mice; Phenobarbital; Porphobilinogen Synthase; Porphyrias; Porphyrias, Hepatic; Protoporphyria, Erythropoietic
PubMed: 30737139
DOI: 10.1016/j.ymgme.2019.01.007 -
Molecular Genetics and Metabolism Nov 2019The acute porphyrias are characterized by defects in heme synthesis, particularly in the liver. In some affected patients, there occurs a critical deficiency in a...
BACKGROUND AND AIMS
The acute porphyrias are characterized by defects in heme synthesis, particularly in the liver. In some affected patients, there occurs a critical deficiency in a regulatory heme pool within hepatocytes that leads to up-regulation of 5-aminolevulinic acid [ALA] synthase-1, which is the first and normally rate-controlling enzyme in the pathway. In earlier work, we described defects in mitochondrial functions in cultured skin fibroblasts from patients with acute intermittent porphyria [AIP]. Others described defects in livers of murine models of AIP. Here, we explored mitochondrial energetics in peripheral blood mononuclear cells [PBMCs] and platelets in persons with AIP and hereditary coproporphyria [HCP]. Our hypotheses were that there are deficits in bioenergetic capacity in acute porphyrias and that subjects with more severe acute porphyria have more pronounced reductions in mitochondrial oxygen consumption rates [OCR].
METHODS
We studied 17 subjects with acute hepatic porphyrias, 14 with classical AIP, one with severe AIP due to homozygous deficiency of hydroxymethylbilane synthase [HMBS], 2 with HCP, and 5 non-porphyric controls. We collected peripheral blood, isolated PBMCs, which we assayed either immediately or after frozen storage [80C] for up to 14 days. Using Seahorse XF-24-3, we measured OCR in the presence of glucose + pyruvate under basal condition, and after additions of oligomycin, carbonylcyanide p-trifluoromethoxyphenylhydrazone [FCCP], and antimycin+rotenone.
RESULTS
Most subjects [13/17, 76%] were female. Subjects with moderate/severe symptoms associated with acute porphyria had significantly lower basal and maximal-OCR than those with no/mild symptoms who were the same as controls. We observed significant inverse correlation between urinary porphobilinogen [PBG] excretion and OCR. The subject with homozygous AIP had a much lower-OCR than his asymptomatic parents.
SUMMARY/CONCLUSIONS
Results support the hypothesis that active acute hepatic porphyria is characterized by a deficiency in mitochondrial function that is detectable in PBMCs, suggesting that limitations in electron transport and ATP production exist in such individuals.
Topics: Adenosine Triphosphate; Adult; Aged; Aged, 80 and over; Blood Platelets; Coproporphyria, Hereditary; Electron Transport; Energy Metabolism; Female; Heme; Humans; Infant; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Oxygen; Pilot Projects; Porphyria, Acute Intermittent
PubMed: 31153822
DOI: 10.1016/j.ymgme.2019.05.010 -
Journal of Hematology Mar 2017Hereditary coproporphyria (HCP) is the third most common of the acute porphyrias, after acute intermittent porphyria and variegate porphyria. It is caused by decreased...
Hereditary coproporphyria (HCP) is the third most common of the acute porphyrias, after acute intermittent porphyria and variegate porphyria. It is caused by decreased activity of the sixth step in the heme biosynthetic pathway. Here we present a case of a woman with HCP who has experienced a wide variety of symptoms over several years. Most interesting among these is a unique neuropsychiatric syndrome marked by severe confusion, disorientation, and abnormal behavior. The literature is reviewed regarding the pathophysiology and management of neuropsychiatric manifestations of porphyria. As many other diagnoses are often considered before the diagnosis of porphyria is made, clinicians should keep in mind the highly variable neurological and psychiatric symptoms of porphyria.
PubMed: 32300387
DOI: 10.14740/jh315w -
The Journal of Clinical Investigation Sep 1983Three siblings with intense jaundice and hemolytic anemia at birth were found to excrete a high level of coproporphyrin in their urine and feces; the pattern of fecal...
Three siblings with intense jaundice and hemolytic anemia at birth were found to excrete a high level of coproporphyrin in their urine and feces; the pattern of fecal porphyrin excretion was atypical for hereditary coproporphyria because the major porphyrin was harderoporphyrin (greater than 60%; normal value is less than 20%). The lymphocyte coproporphyrinogen III oxidase activity of each patient was 10% of control values, which suggests a homozygous state. Both parents showed only mild abnormalities in porphyrin excretion and lymphocyte coproporphyrinogen III oxidase activity decreased to 50% of normal values, as is expected in heterozygous cases of hereditary coproporphyria. Kinetic parameters of coproporphyrinogen III oxidase from these patients were clearly modified, with a Michaelis constant 15-20-fold higher than normal values when using coproporphyrinogen or harderoporphyrinogen as substrates. Maximal velocity was half the normal value, and we also observed a marked sensitivity to thermal denaturation. The possibility that a mutation affecting the enzyme on the active center which is specifically involved in the second decarboxylation (from harderoporphyrinogen to protoporphyrinogen) was eliminated by experiments on rat liver that showed that coproporphyrinogen and harderoporphyrinogen were metabolized at the same active center. The pattern of porphyrin excretion and the coproporphyrinogen oxidase from the three patients exhibited abnormalities that were different from the abnormalities found in another recently described homozygous case of hereditary coproporphyria. We suggest naming this variant of coproporphyrinogen oxidase defect "harderoporphyria."
Topics: Animals; Coproporphyrinogen Oxidase; Decarboxylation; Feces; Female; Humans; Infant, Newborn; Kinetics; Liver Diseases; Lymphocytes; Male; Mutation; Porphyrias; Porphyrinogens; Porphyrins; Rats
PubMed: 6886003
DOI: 10.1172/JCI111039 -
Journal of Internal Medicine Jun 2022The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict...
BACKGROUND
The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex.
METHODS
All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987-2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers.
RESULTS
We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3-59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG (n = 157) had an annual PLC incidence of 1.8%.
CONCLUSION
This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.
Topics: Cohort Studies; Humans; Liver Neoplasms; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias; Porphyrias, Hepatic
PubMed: 35112415
DOI: 10.1111/joim.13463