Congenital erythropoietic porphyria: report of a novel mutation with absence of clinical manifestations in a homozygous mutant sibling.

In a Palestinian family, four siblings were shown to express typical and severe congenital erythropoietic porphyria (CEP). A new mutation of the uroporphyrinogen III synthase (UROS) gene was evidenced by systematic sequencing of the UROS gene: the substitution of serine by proline at the amino acid residue 47 (S47P) was present at the homozygous state in the four patients. The mother was heterozygous, the father was not examined. Surprisingly, in one unaffected sister, UROS activity was markedly deficient and UROS gene analysis showed a homozygous mutant profile. The deleterious role of the mutant S47P protein on UROS activity was demonstrated by prokaryotic expression. This observation is the first report of a healthy status associated with homozygosity for a mutation of UROS gene in a severely affected family. We then draw hypotheses to explain the protective phenotype in the homozygous healthy subject.