MOLECULAR CHARACTERIZATION OF HOMOZYGOUS VARIEGATE PORPHYRIA

Variegate porphyria (VP) is a low penetrance, autosomal dominant disor der that results from partial deficiency of protoporphyrinogen oxidase (PPOX) activity caused by mutation in the PPOX gene. The rare homozyg ous variant of VP is characterized by severe PPOX deficiency, onset of photosensitization by porphyrins in early childhood, skeletal abnorma lities of the hand and, less constantly, short stature, mental retarda tion and convulsions. We have identified PPOX mutations on both allele s of five of the 11 unrelated patients with homozygous VP reported to date. Two patients were homoallelic for missense mutations (D349A and A433P), white three were heteroallelic. Functional analysis by prokary otic expression showed that the D349A and A433P and one missense mutat ion in each of the three heteroallelic patients (G358R in two patients and A219KANA) preserved some PPOX activity (9.5-25% of wild-type). Mu tations on the other altere of the heteroallelic patients abolished or markedly decreased activity. There was no relation between genotype a ssessed by functional analysis and the presence or severity of non-cut aneous manifestations. The mutations were absent from 104 unrelated pa tients with autosomal dominant VP. Our findings define the molecular p athology of homozygous VP and suggest that mild PPOX mutations occur i n the general population but have very low or no clinical penetrance i n heterozygotes.