APOLIPOPROTEIN B-100, FAMILIAL LIGAND-DEFECTIVE
APOLIPOPROTEIN B-100, FAMILIAL DEFECTIVE
HYPERCHOLESTEROLEMIA, FAMILIAL, DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B
Higgins et al. (1975) described father and daughter with hypercholesterolemia which appeared to be due to an abnormality in LDL such that it did not interact properly with the receptor. The proband's leukocytes showed normal suppression of HMG ... Higgins et al. (1975) described father and daughter with hypercholesterolemia which appeared to be due to an abnormality in LDL such that it did not interact properly with the receptor. The proband's leukocytes showed normal suppression of HMG CoA reductase activity when exposed to lipoprotein from sources other than the 2 patients. (Perhaps a letter designation can be used for the several forms of familial hypercholesterolemia. Roman numbers run the risk of confusion with the Fredrickson types of hyperlipoproteinemia.) The Ag system of lipoprotein types (see 107730) represents variation in the apoprotein of LDL and each LDL molecule may contain 2 identical protein subunits. Thus, the locus of this mutation might be the Ag locus (if the abnormal binding is due to a change in the protein of LDL). Vega and Grundy (1986) showed that some patients with hypercholesterolemia have reduced clearance of LDL not because of decreased activity of LDL receptors but because of a defect in the structure (or composition) of LDL that reduces its affinity for receptors. In 5 of 15 patients, turnover rates indicated that clearance of autologous LDL was significantly lower than for homologous normal LDL. In these 5 patients, autologous LDL appeared to be a poor ligand for LDL receptors. The authors did not carry the investigations far enough to determine whether abnormality in the primary structure of apoB100 accounted for the poor binding to receptors. Innerarity et al. (1987) found that moderate hypercholesterolemia could be attributed to defective receptor binding of a genetically altered apoB100 to the LDL receptor; they designated the disorder 'familial defective apolipoprotein B100.' The proband of the family studied by Innerarity et al. (1987) was described earlier by Vega and Grundy (1986). A finding of the same abnormality in several of the proband's first-degree relatives indicated the inherited nature of the defect. Weisgraber et al. (1988) found an antibody with an isotope between residues 3350 and 3506 of apoB that distinguished abnormal LDL from normal LDL in this disorder; the antibody MB47 bound with a higher affinity to abnormal LDL. Thus, an assay was provided for screening large populations for this disorder. Goldstein (1987) stated that an abnormality in LDL was not confirmed in his or in a second laboratory. The putatively abnormal LDL tested normal in all of their culture systems and also tested normal when injected into animals. Myant et al. (1976) found that the putatively abnormal LDL behaved in a normal fashion in various in vivo and in vitro assays. Goldstein (1987) stated further that although no documented cases of hypercholesterolemia due to mutations in the apoB gene were known, he 'would not be surprised if such cases were discovered any time--now that cDNA probes for the apoB of LDL are widely available.' The prophecy was fulfilled by the demonstration of familial hypercholesterolemia due to defective apoB-100. Illingworth et al. (1992) found that LDL cholesterol was reduced after administration of lovastatin in 12 hypercholesterolemic patients from 10 unrelated families with familial defective apoB100. Hansen et al. (1997) attempted to identify determinants of phenotypic variation in patients heterozygous for familial defective apolipoprotein B in 205 patients: 73 from Germany, 87 from the Netherlands, and 45 from Denmark. In addition, they attempted to assess whether the clinical phenotype of familial defective apoB differs from that of familial hypercholesterolemia. Besides age, sex, and geographic origin, variation in the LDLR gene was found to be the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene was associated with total cholesterol and LDL variation in women. The expected association of APOE genotypes with cholesterol concentrations was also seen. With regard to clinical expression, familial defective APOB patients had lower total cholesterol and LDL cholesterol levels and a lower prevalence of cardiovascular disease than did 101 Danish patients with familial hypercholesterolemia.
Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia (143890) results from defects in the cell surface receptor that removes LDL particles from plasma (LDLR; 606945). Innerarity et al. (1987) demonstrated the genetic heterogeneity of ... Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia (143890) results from defects in the cell surface receptor that removes LDL particles from plasma (LDLR; 606945). Innerarity et al. (1987) demonstrated the genetic heterogeneity of autosomal dominant hypercholesterolemia by reporting hypercholesterolemic patients with normal LDLR activity and defective apolipoprotein B-100 (APOB; 107730) that displayed low affinity for its receptor. This novel form of the disorder was called familial ligand-defective apolipoprotein B-100, or type B familial hypercholesterolemia, because mutations were identified in the APOB gene (e.g., R3500Q; 107730.0009). Classic FH and the ligand-defective form (type B) map to chromosomes 19 and 2, respectively. In a 46-year-old woman of Celtic and Native American ancestry with primary hypercholesterolemia and pronounced peripheral vascular disease, Pullinger et al. (1995) identified heterozygosity for a missense mutation in the APOB gene (R3531C; 107730.0017). Screening of 1,560 individuals revealed an unrelated man of Italian ancestry with coronary heart disease and elevated triglyceride and LDL cholesterol levels who carried the same R3531C mutation; the mutation was also detected in 8 other members of the families of the 2 patients. LDL from R3531C-positive individuals had an affinity for the LDL receptor that was 63% of that of control LDL, compared to 91% for unaffected family members and 36% for patients heterozygous for the R3500Q mutation (107730.0009).