A mouse model for South African (R59W) variegate porphyria: construction and initial characterization.

Variegate porphyria is inherited as an autosomal dominant disease with variable penetrance. It is characterized clinically by photocutaneous sensitivity and acute neurovisceral attacks, and biochemically by abnormal porphyrin excretion in the urine and feces. While the world-wide incidence of variegate porphyria is relatively low, in South Africa it is one of the most common genetic diseases in humans. Due to the large number of patients with variegate porphyria in South Africa, and the fact that variegate porphyria is representative of both the so-called "acute" and the "photocutaneous" porphyrias, it would be valuable to have an animal model in which to study the disease. In this study we have produced a mouse model of "South African" variegate porphyria with the R59W mutation in C57/BL6 mice via targeted gene replacement. Hepatic protoporphyrinogen oxidase activity was reduced by approximately 50% in mice heterozygous for the mutation. Urine and fecal samples from these mice, in the absence of exogenous inducers of hepatic haem synthesis, contain elevated concentrations of porphyrins and porphyrin precursors in a pattern similar to that found in human variegate porphyric subjects. Bypassing the rate-limiting step in haem biosynthesis by feeding 5-aminolevulinic acid to these mice, results in an accentuated porphyrin excretory pattern characteristic of the variegate porphyric phenotype and urinary porphobilinogen is increased significantly. This initial characterization of these mice suggest that they are a good model for variegate porphyria at the biochemical level.