Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two afrikaner founder LDL receptor mutations

Two common founder-related gene mutations that affect the low-density lipoprotein receptor (LDLR) are responsible for ≈80% of familial hypercholesterolemia (FH) in South African Afrikaners. The FH Afrikaner-1 (FH1) mutation (Asp206→Glu) in exon 4 results in defective receptors with ≈20% of normal activity, whereas the FH Afrikaner-2 (FH2) mutation (Val408→Met) in exon 9 completely abolishes LDLR activity (<2% normal activity). We analyzed the contribution of these mutations and other factors on the variation of hypercholesterolemia and clinical features in Afrikaner FH heterozygotes. The type of FH mutation, plasma triglyceride levels, and age of patients each contributed significantly to the variation in hypercholesterolemia, whereas smoking status, high-density lipoprotein cholesterol levels, and gender had no influence. Although all FH heterozygotes had frank hypercholesterolemia, patients with the FH1 mutation had significantly lower cholesterol levels than those with the FH2 mutation. FH1 heterozygotes also tended to have milder clinical features. The differences between the two FH groups could not be explained by a difference in the common apolipoprotein E variants. This study demonstrates that mutational heterogeneity in the LDLR gene influences the phenotypic expression of heterozygous FH.