Variegate porphyria in Western Australian Aboriginal patients.

BACKGROUND: Survivors of shipwrecks along the Western Australian coast may have introduced a mutation for variegate porphyria into the Aboriginal population prior to first settlement. AIMS: To assess the mutations responsible for variegate porphyria in Western Australian Aboriginal patients, particularly the R59W mutation, which is the most common cause of variegate porphyria in South Africa. METHODS: New cases of porphyria were diagnosed by biochemical separation of porphyrin subtypes. Single-stranded conformation polymorphism analysis and DNA sequencing of the protoporphyrinogen oxidase gene was performed on Aboriginal patients to define possible causative mutation sites. RESULTS: Of the 296 new cases of porphyria diagnosed in Western Australia from 1978 to 1998, six had biochemically proven variegate porphyria. Three of those cases occurred in Aboriginal patients. Evidence for a possible fourth Aboriginal case of variegate porphyria is described. The R59W founder mutation responsible for over 90% of variegate porphyria in South Africa was excluded. Two new mutations that predicted amino acid substitutions with significant effects on enzyme function were detected in conserved regions of the protoporphyrinogen oxidase gene in one Aboriginal variegate porphyria patient and the possible fourth case. CONCLUSION: Results suggest that the mutations causing variegate porphyria in the Western Australian Aboriginal population occur sporadically and were not inherited from shipwrecked sailors.

Single nucleotide polymorphisms of the protoporphyrinogen oxidase gene: inter-population heterogeneity of allelic variation.

Five single nucleotide polymorphisms (SNPs) in the protoporphyrinogen oxidase gene (PPOX) were used for inter-population comparisons of six South African populations and two non-South African Caucasian populations. Novel polymorphisms identified in the promoter region and exon 11 of the PPOX gene, as well as three known variants in exon 1 and intron 2, were analysed using single-strand conformation polymorphism (SSCP) and restriction enzyme analyses. Significant population differences were found for four of the five polymorphisms analysed. A G-to-A transition was found at nucleotide position -1081 and is the first polymorphism to be identified in the 5' promoter region of the gene. A novel A-to-C substitution at nucleotide position 3880 in exon 11 was not detected in subjects of European descent. This study represents the first inter-population comparison of allelic variation at the PPOX locus. The significant differences observed between populations demonstrate the importance of population considerations when marker association studies are performed at this locus.