Compound heterozygous familial hypercholesterolemia and familial defectiveapolipoprotein B-100 produce exaggerated hypercholesterolemia

Background: Familial hypercholesterolemia (FH) and familial defective apoli poprotein B-100 (FDB) represent ligand-receptor disorders that are compleme ntary. Individuals with both FH and FDB are unusual. We report a family wit h both disorders and the impact of the mutations on the phenotypes of the f amily members. Methods: We used single strand conformation polymorphism (SSCP) and denatur ing gradient gel electrophoresis (DGGE) for genetic analysis of all 18 exon s and the promoter region of the LDL receptor and DGGE for genetic analysis of the apolipoprotein B-100 (apo B-100) gene. The functional significance of the apo B-100 mutation was studied using a U937 cell proliferation assay . Fasting serum lipid profiles were determined for the index case and seven first-degree relatives. Results: One of the patient's sisters had a missense mutation (Asp(407)-->L ys) in exon 9 of the LDL receptor and a serum LDL-cholesterol concentration of 4.07 mmol/L, Four other first-degree relatives had hyperlipidemia but n o LDL-receptor mutation. However, these subjects had a mutation of the apo B-100 gene (Arg(3500)-->Trp). The cell proliferation rate of U937 cells fed with LDL from other subjects with the same mutation was fourfold less than that of controls. The index case had both FH- and FDB-related mutations. H er serum LDL-cholesterol (9.47 mmol/L) was higher than all other relatives tested. Conclusions: Existence of both FH and FDB should be considered in families with LDL-receptor mutations in some but not all individuals with hyperchole sterolemia or when some individuals in families with FH exhibit exaggerated hypercholesterolemia. (C) 2001 American Association for Clinical Chemistry .