Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria.

Hereditary coproporphyria (HCP) is the least common of the autosomal dominant acute hepatic porphyrias. It results from mutations in the CPO gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. A few patients have also 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 a neonatal hemolytic anemia that is known as "harderoporphyria"; mutations on both alleles elsewhere in the gene give rise to the "homozygous" variant of HCP. The molecular relationship between these disorders and HCP has not been defined. We describe the molecular investigation and clinical features of 17 unrelated British patients with HCP. Ten novel and four previously reported CPO mutations, together with three previously unrecognized single-nucleotide polymorphisms, were identified in 15 of the 17 patients. HCP is more heterogeneous than other acute porphyrias, with all but one mutation being restricted to a single family, with a predominance of missense mutations (10 missense, 2 nonsense, 1 frameshift, and 1 splice site). Of the four known mutations, one (R331W) has previously been reported to cause disease only in homozygotes. Heterologous expression of another mutation (R401W) demonstrated functional properties similar to those of the K404E harderoporphyria mutation. In all patients, clinical presentation was uniform, in spite of the wide range (1%-64%) of residual coproporphyrinogen oxidase activity, as determined by heterologous expression. Our findings add substantially to knowledge of the molecular epidemiology of HCP, show that single copies of CPO mutations that are known or predicted to cause "homozygous" HCP or harderoporphyria can produce typical HCP in adults, and demonstrate that the severity of the phenotype does not correlate with the degree of inactivation by mutation of coproporphyrinogen oxidase.