Molecular characterisation of a low-frequency mutation in exon 8 of the human low-density lipoprotein receptor gene.

The prevalence of familial hypercholesterolaemia (FH), an autosomal dominant disease characterised by raised low-density lipoprotein (LDL) cholesterol levels, is at least five times higher in the white Afrikaner population than in most other population groups in the world. A founder gene effect has been suggested to explain this abnormally high frequency. Detection of a polymorphic Stu I site in the 5' region of the LDL receptor gene and association of both restriction fragment length polymorphism alleles with FH in Afrikaners, indicated the existence of at least two founder members for the disease in this population. DNA from a hetero-allelic FH homozygote from this South African group has been analysed through genomic cloning and sequencing. The DNA polymorphic site is caused by a single guanine to adenine transition within exon 8 of the LDL receptor gene and can be used in the determination of haplotype-associated defects.