RESUMEN
Variegate porphyria (VP) is caused by the founder-type protoporphyrinogen oxidase (PPOX) gene mutation R59W in the majority of South African patients. VP is inherited as an autosomal dominant disease with incomplete penetrance and no genotype-phenotype association has been established to date. In an attempt to determine whether a relatively common mutation in the promoter region of the gene (-1081G>A) represents a low-expression allele that may influence clinical manifestation of the disease when inherited from the non-carrier (R59W-negative) parent, we have studied the effect of the mutated allele using an in vitro luciferase assay. Haplotype analysis was furthermore used to evaluate the added information obtained by considering the possible influence of this mutation in combination with a polymorphism in intron 2 (206G>C) of the gene in a genotype-phenotype correlation study. Although the mutation at nucleotide -1081 resulted in a significant reduction in transcriptional activity relative to the reference wild type, no evidence could be obtained that a specific haplotype inherited from the normal parent affects clinical expression of the disease. We thus conclude that other factors such as modifier loci unrelated to the PPOX gene may determine clinical manifestation of VP.