title: Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria.
abstract: 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.
authors.affiliation: INSERM U656 and Centre Français de Porphyries, Université Paris VII, Hôpital Louis Mourier, Colombes, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schmitt
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.forename: Eva
authors.initials: E
authors.lastname: Malonova
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lamoril
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Camadro
authors.forename: Magali
authors.initials: M
authors.lastname: Flamme
authors.forename: Christian
authors.initials: C
authors.lastname: Rose
authors.forename: Said
authors.initials: S
authors.lastname: Lyoumi
authors.forename: Vasco
authors.initials: V
authors.lastname: Da Silva
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Bernard
authors.initials: B
authors.lastname: Grandchamp
authors.forename: Carole
authors.initials: C
authors.lastname: Beaumont
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
mesh_terms: D000595:Amino Acid Sequence; D046349:Coproporphyria, Hereditary / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D003304:Coproporphyrinogen Oxidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D015870:Gene Expression; D006418:Heme / Q000096:biosynthesis; D006801:Humans; D019190:Iron Overload / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D017094:Porphyrias, Hepatic / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D017433:Protein Structure, Secondary; D017385:Sequence Homology
chemical_list: D006418:Heme; D003304:Coproporphyrinogen Oxidase