Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.

Lipid and lipoprotein concentrations in plasma generally reflect complex influences of multiple genetic loci. Even an autosomal dominant disorder, familial hypercholesterolemia (FH), is characterized by phenotypic heterogeneity, as low-density lipoprotein (LDL) levels vary widely within the same pedigree. Molecular screening for LDL receptor ( LDLR) mutations among 75 patients with clinically apparent FH led to identification of a novel splice-site mutation (IVS14+1 G>A) shared by 14 patients. Genealogical research confirmed that all 14 carriers were part of the same 1135-member pedigree with a common ancestor. The mutation resulted in an abruptly truncated LDLR protein, reducing functional LDLR activity by half in heterozygous carriers of the mutant allele. Of the 208 members of the kindred who were screened for the presence of this LDLR mutation, we identified 94 carriers and 114 noncarriers. Nine principal apolipoprotein genes that might affect LDL cholesterol differentially according to LDL-receptor status were examined in this pedigree. Strikingly lower total cholesterol and LDL-cholesterol values were observed among the majority of the LDLR mutation carriers who were simultaneously homozygous for the -265C variant of apoA-II (total cholesterol: 324 +/- 8 vs 244 +/- 19 mg/dl, P = 0.0015; LDL-cholesterol: 237 +/- 8 vs 155 +/- 18 mg/dl, P = 0.0008). In vitro transfection assays showed that transcriptional activity of the apoA-II promoter was reduced by 30% in the -265C variant as compared with the -265T variant. We thus concluded that one variant of the apoA-II gene was associated with reduced plasma LDL cholesterol only in FH patients.