SOUTH-AFRICAN FOUNDER MUTATIONS IN THE LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE CAUSING FAMILIAL HYPERCHOLESTEROLEMIA IN THE DUTCH POPULATION

In South African Afrikaners, three point mutations in the gene coding for the low-density lipoprotein (LDL)-receptor are responsible for mor e than 95% of the cases of familial hypercholesterolemia (FH). To inve stigate whether one or more of these mutations originated in The Nethe rlands, a large group of Dutch heterozygous FH patients was screened f or the presence of these three mutations. Of these, a missense mutatio n in exon 9 of the LDL-receptor gene, resulting in a substitution of M et for Val(408), responsible for 15% of FH in Afrikaners, was found in 19 (1.5%) of 1268 FH patients of Dutch descent. Nine of the patients carrying the exon 9 mutation on one allele shared the LDL-receptor DNA haplotype with an FH patient from South Africa, who was homozygous fo r the same mutation. This would suggest that the mutation in these pat ients and in the South African patient have a common ancestral backgro und. The remaining ten FH patients all shared a common haplotype, part ly identical to the Afrikaner haplotype, which chould have arisen from a single recombinational event. This mutation has not been described in persons other than of Dutch ancestry and supports the hypothesis th at this mutation in exon 9 originated in The Netherlands and, in all l ikelihood, was introduced into South Africa by early Dutch settlers in the seventeenth century.