PHENOTYPIC VARIATION AMONG FAMILIAL HYPERCHOLESTEROLEMICS HETEROZYGOUS FOR EITHER ONE OF 2 AFRIKANER FOUNDER LDL RECEPTOR MUTATIONS

Two common founder-related gene mutations that affect the low-density lipoprotein receptor (LDLR) are responsible for almost-equal-to 80% of familial hypercholesterolemia (FH) in South African Afrikaners. The F H Afrikaner-1 (FH1) mutation (AsP206 --> Glu) in exon 4 results in def ective receptors with almost-equal-to 20% of normal activity, whereas the FH Afrikaner-2 (FH2) mutation (Val408 --> Met) in exon 9 completel y abolishes LDLR activity (<2% normal activity). We analyzed the contr ibution of these mutations and other factors on the variation of hyper cholesterolemia and clinical features in Afrikaner FH heterozygotes. T he type of FH mutation, plasma triglyceride levels, and age of patient s each contributed significantly to the variation in hypercholesterole mia, whereas smoking status, high-density lipoprotein cholesterol leve ls, and gender had no influence. Although all FH heterozygotes had fra nk hypercholesterolemia, patients with the FHI mutation had significan tly lower cholesterol levels than those with the FH2 mutation. FHI het erozygotes also tended to have milder clinical features. The differenc es between the two FH groups could not be explained by a difference in the common apolipoprotein E variants. This study demonstrates that mu tational heterogeneity in the LDLR gene influences the phenotypic expr ession of heterozygous FH.