D R van der Westhuyzen

Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners.

Familial hypercholesterolemia (FH), an autosomal dominant disease caused by mutations in the LDL receptor gene, is five times more frequent in the Afrikaner population of South Africa than it is in the population of the United States and Europe. It has been proposed that the high frequency is due to a founder effect. In this paper, we characterized 24 mutant LDL receptor alleles from 12 Afrikaner individuals homozygous for FH. We identified two mutations that together makeup greater than 95% of the mutant LDL receptor genes represented in our sample. Both mutations were basepair substitutions that result in single-amino acid changes. Each mutation can be detected readily with the polymerase chain reaction and restriction analysis. The finding of two common LDL receptor mutations in the Afrikaner FH homozygotes predicts that these mutations will predominate in the Afrikaner population and that the high frequency of FH is due to a founder effect. The increased incidence of ischemic heart disease in the Afrikaner population may in part be due to the high frequency of these two mutations in the LDL receptor gene.

4.P.317 Alternative forms of the scavenger receptor BI (SR-BI)

The class B, type I scavenger receptor has been implicated as a receptor for high density lipoprotein (HDL). We have isolated a murine cDNA clone encoding an alternative form of SR-BI that differs in the putative cytoplasmic domain of the receptor. This variant form, likely the result of alternative mRNA splicing, is designated SR-BI.2. SR-BI.2 mRNA was detected in mouse tissues known to express SR-BI and tissue-specific differences in the relative abundance of SR-BI.2 were apparent. In mouse adrenal glands, SR-BI.2 represented approximately one-third of total SR-BI mRNA, whereas in mouse testes, SR-BI.2 represented the major mRNA species (79% of total). SR-BI.2 was also detected in the human cell lines examined, namely HeLa, HepG2, and THP-1 cells. CHO cells transfected with the mouse SR-BI.2 cDNA expressed significant levels of SR-BI.2 protein and acquired the ability to take up fluorescent lipid (DiI) from DiI-HDL. Alternative splicing of SR-BI represents a potentially important process for the regulation of SR-BI expression and function.