THE GENETIC-BASIS OF SCARSDALE-GOURMET-DIET VARIEGATE PORPHYRIA - A MISSENSE MUTATION IN THE PROTOPORPHYRINOGEN OXIDASE GENE

The porphyrias are disorders of porphyrin or porphyrin-precursor metab olism that result from inherited or acquired aberrations in the contro l of the porphyrin-heme biosynthetic pathway, Variegate porphyria (VP) , one of the acute hepatic porphyrias, is characterized by a partial r eduction in the activity of protoporphyrinogen oxidase (PPO), and rece ntly, mutations in the PPO gene on chromosome 1q22-23 have been descri bed. Our purpose was to identify the underlying genetic lesion in a se verely affected patient with VP and to detect the silent mutation carr iers in her family. The disease in this patient was precipitated by ca rbohydrate restriction as outlined in the ''Scarsdale Gourmet Diet''. Our mutation detection and confirmation strategy included PCR, automat ed sequencing, and restriction enzyme digestion. We identified a misse nse mutation in the patient and five family members. The mutation cons isted of a previously unreported C-to-T transition in exon 5 of the PP O gene, resulting in the substitution of arginine by cysteine, designa ted R152C, This arginine residue is evolutionarily highly conserved in humans, mice, bacteria, yeast, and plants, indicating the importance of this residue in PPO, Our study established that a missense mutation in the PPO gene was the underlying mutation in this patient with VP a nd explained the occurrence of the phenotype in this family.