Mutations in the PPOX Gene in South African families

Exon	Mutation	Clinical expression
2	H20P	Typical VP.
2	L15F	Typical VP. Mutation identified in UK patients with VP and probably imported to South Africa by a British settler.
3	R59W	Typical VP. The South African founder mutation imported to the Cape in 1688 and now widespread in the population. Also identified in the Netherlands, where it is rare, and shown by haplotype analysis to be genetically related to the South African population. Also the mutation found on one allele of all four South African patients with compound heterozygous ("homozygous") VP.
5	R138P	Less severe mutation which does not cause typical VP in heterozygotes, but found in trans to the R59W mutation in two mixed-race sisters with compound heterozygous VP. These sisters are relatively less-severely affected, in keeping with a mild mutation.
6	537 delAT	Typical VP in a mixed-race family.
6	R168C	Less severe mutation which does not cause typical VP in heterozygotes, but was found in trans to the R59W mutation in a patient with severe compound heterozygous VP.
7	C769delG; 770T>A	Typical VP in a mixed-race family.
8	V290M	Typical VP in an indigenous African family.
10	Y348C	Less severe mutation which does not cause typical VP in heterozygotes, but was found in trans to the R59W mutation in a patient with severe compound heterozygous VP.
11	Q375X	Typical VP in a Canadian family settled in South Africa.

These are the mutations in the protoporphyrinogen oxidase (PPOX) gene which we have identified in South African families with variegate porphyria. Three are mutations which produce a PPOX protein with considerable residual enzymatic activity, and for this reason are not associated with disease in heterozygotes. However, when found in trans* to the R59W mutation, which produces a non-functional PPOX protein, the patient's enzyme activity is drastically reduced—in the order of about 5% of normal, compared with the 50% of a typical VP heterozygote—resulting in a severe phenotype which we know as homozygous VP. (The patients are more correctly termed compound heterozygotes.)

* in trans: the technical term meaning that the mutation is found on the other of the two alleles for PPOX, not on the same allele as the R59W mutation.