Martin C.1, Gouya L.1, Da Silva V.1, Camadro J.M.2, Puy H.1, Deybach J.C.1
1Centre Français des Porphyries, INSERM U409, UFR X. Bichat, Hopital Louis Mourier, Colombes, France, 2Laboratoire d'Ingénierie des Protéines et Contrôle Métabolique, Département Biologie des Génomes, Institut Jacques Monod, CNRS UMR 7592, Université Paris VI-VII, Paris, France
Hereditary coproporphyria (HCP), an autosomal dominant acute hepatic porphyria, results from mutations in the CPO gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. A few patients have 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 an unifying syndrome in which hematologic disorders predominate: "harderoporphyria". Heterologous expression of another mutation (R401W) demonstrated functional properties to those of the K404E harderoporphyria mutation. Mutations on both alleles elsewhere in the gene give rise to the "homozygous" variant of HCP. The molecular relationship between the single CPO gene and these two different phenotypes (harderoporphyria and HCP) has not been defined and biochemical bases remained unexplained. We describe the molecular investigation and clinical features of harderoporphyric families reported so far, including a novel one. Investigations performed both in vivo and in vitro by heterologous expression studies after hydrophobic cluster analysis (HCA) of the secondary structure of CPO enzyme demonstrate that only few missense mutations restricted to 5 aminoacid encoded by exon 6 and localised in a hinge region between two b sheets may lead to harderoporphyrin accumulation and subsequently harderoporphyric phenotype: D400, R401, G402, T403, K404. Moreover, all other type of mutations or missense mutations mapped elsewhere throughout the CPO gene lead to coproporphyrin accumulation and subsequently typical HC. Our findings add substantially to knowledge of molecular and biochemical bases responsible for the specific hematologic clinical manifestations of harderoporphyria and demonstrate that the type and location of the mutations in the CPO gene clearly modulate of phenotype.