MOLECULAR-BASIS OF VARIEGATE PORPHYRIA - A DE-NOVO INSERTION MUTATIONIN THE PROTOPORPHYRINOGEN OXIDASE GENE

The porphyrias are disorders that result from the inherited or acquire d dysregulation of one of the eight enzymes in the heme biosynthetic p athway. Variegate porphyria (VP) is characterized by deficiencies in p rotoporphyrinogen oxidase (PPO) and has recently been genetically link ed (Z = 6.62) to the PPO gene on chromosome 1q21. In this study, we ha ve identified two sequence variants in the PPO gene in a family with V P. The first is a neutral polymorphism at the -47 position of intron 2 ; this polymorphism is present in the general population and is unlike ly to underlie the VP phenotype. The second is a mutation in the PPO g ene in a patient with VP; the mutation consists of an apparently de no vo 2-bp insertion in exon 3 of PPO and results in a frameshift and dow nstream premature termination codon. These data establish that a frame shift mutation in PPO is the underlying mutation in this patient with VP and explain the sporadic occurrence of the phenotype in this family .