Human Molecular Genetics Advance Access originally published online on September 13, 2005
Human Molecular Genetics 2005 14(20):3089-3098; doi:10.1093/hmg/ddi342
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Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria
1INSERM U656 and Centre Français des Porphyries, Université Paris VII, Hôpital Louis Mourier, 92701 Colombes, France, 2Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Ambroise Paré, Faculté de Médecine Paris – Ile de France Ouest, 92100 Boulogne-Billancourt, France, 3Department of Pediatrics, Faculty of Medicine I, Charles University, Praha, Czech Republic, 4Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Département de Biologie des Génomes, Institut Jacques Monod, CNRS UMR7592, Université Paris VI et VII, 75005 Paris, France, 5Service de Dermatologie, Cliniques Universitaires Saint-Luc, 1200 Bruxelles, Belgium and 6Service des Maladies du Sang, Hôpital Claude Huriez, 59037 Lille, France
* To whom correspondence should be addressed at: Centre Français des Porphyries – INSERM U656, Hôpital Louis Mourier, 92701 Colombes Cedex, France. Tel: +33 147606331; Fax: +33 147606703; Email: jean-charles.deybach{at}lmr.ap-hop-paris.fr
Received July 4, 2005; Accepted September 7, 2005
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.