RECURRENT LDL-RECEPTOR MUTATION CAUSES FAMILIAL HYPERCHOLESTEROLEMIA IN SOUTH-AFRICAN COLOUREDS AND AFRIKANERS

Three low-density lipoprotein receptor (LDLR) gene mutations were prev iously shown to cause familial hypercholesterolaemia (FH) in up to 90% of affected Afrikaners. Association of each mutation with a single ch romosomal background provided molecular genetic evidence that the prop osed 'founder gene effect' was responsible for the high prevalence of FH among white Afrikaners. In this study we report the identification of the FH Afrikaner-2 (FH2) mutation, Val(408) to Met, in the so-calle d coloured population of South Africa, a people of mixed ancestry, wit h rapid non-radioactive methods for mutation detection. Haplotype anal ysis with polymorphisms on both sides of the FH2 mutation indicated th at the identical LDLR gene mutations found in two different South Afri can population groups were caused by independent events at a potential CpG mutational 'hot spot'. The allelic variation giving rise to the d ifferent chromosomal backgrounds of the FH2 mutation does not affect t he properties of the abnormal LDLR protein product which causes FH in these subjects, This mutation is thus expected to cause the same sever e form of FH in affected coloureds as was previously demonstrated in A frikaners. Detection of mutant LDLR gene alleles in polymerase chain r eaction products, directly after gel electrophoresis, now allows accur ate presymptomatic diagnosis of the FH2 mutation in FH patients from t wo different South African population groups.