Recurrent LDL-receptor mutation causes familial hypercholesterolaemia in South African coloureds and Afrikaners.

Three low-density lipoprotein receptor (LDLR) gene mutations were previously shown to cause familial hypercholesterolaemia (FH) in up to 90% of affected Afrikaners. Association of each mutation with a single chromosomal background provided molecular genetic evidence that the proposed '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, Val408 to Met, in the so-called coloured population of South Africa, a people of mixed ancestry, with rapid non-radioactive methods for mutation detection. Haplotype analysis with polymorphisms on both sides of the FH2 mutation indicated that the identical LDLR gene mutations found in two different South African population groups were caused by independent events at a potential CpG mutational 'hot spot'. The allelic variation giving rise to the different chromosomal backgrounds of the FH2 mutation does not affect the properties of the abnormal LDLR protein product which causes FH in these subjects. This mutation is thus expected to cause the same severe form of FH in affected coloureds as was previously demonstrated in Afrikaners. Detection of mutant LDLR gene alleles in polymerase chain reaction products, directly after gel electrophoresis, now allows accurate presymptomatic diagnosis of the FH2 mutation in FH patients from two different South African population groups.