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.