Vasco Da Silva

Journal - Human Molecular Genetics

Abstract :

Hereditary coproporphyria (HCP), an autosomal dominant acutehepatic porphyria, results from mutations in the gene that encodescoproporphyrinogen III oxidase (CPO). HCP (heterozygous or rarelyhomozygous) 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 ofHCP. In such patients, the presence of a specific mutation (K404E)on both alleles or associated with a null allele, produces aunifying syndrome in which hematological disorders predominate:‘harderoporphyria’. Here, we report the fifth case(from a third family) with harderoporphyria. In addition, weshow that harderoporphyric patients exhibit iron overload secondaryto dyserythropoiesis. To investigate the molecular basis ofthis peculiar phenotype, we first studied the secondary structureof the human CPO by a predictive method, the hydrophobic clusteranalysis (HCA) which allowed us to focus on a region of theenzyme. We then expressed mutant enzymes for each amino acidof the region of interest, as well as all missense mutationsreported so far in HCP patients and evaluated the amount ofharderoporphyrin in each mutant. Our results strongly suggestthat only a few missense mutations, restricted to five aminoacids encoded by exon 6, may accumulate significant amountsof harderoporphyrin: D400–K404. Moreover, all other typeof mutations or missense mutations mapped elsewhere throughoutthe CPO gene, lead to coproporphyrin accumulation and subsequentlytypical HCP. Our findings, reinforced by recent crystallographicresults of yeast CPO, shed new light on the genetic predispositionto HCP. It represents a first monogenic metabolic disorder whereclinical expression of overt disease is dependent upon the locationand type of mutation, resulting either in acute hepatic or inerythropoietic porphyria.