The apolipoprotein B R3531C mutation: characteristics of 24 subjects from 9 kindreds

Familial ligand-defective apolipoprotein B (apoB) is a group of disorders c aused by mutations in the apoB gene, In this report the R3531C mutation is characterized further using a monoclonal antibody MB19/dynamic laser light scattering technique to measure ratios of Cys(3531) to normal low density l ipoprotein (LDL) particles. All six subjects studied showed a preferential accumulation of particles carrying the defective apoB allotype, We determin ed binding properties of LDL from R3531C heterozygotes by measurement of hi gh-affinity binding to LDL receptors on fibroblasts and its ability promote growth of U937 cells. LDL from R3531C heterozygotes, compared to normal LD L, had 49.3% of the binding affinity and was 74% as effective in a U937 cel l proliferation assay. To identify new probands, we screened 2570 subjects for the R3531C mutation. Nine probands were found with 15 affected relative s. Of the seven haplotypes we uncovered, two were novel, while five were id entical to one initially reported as associated with Cys3531. Three silent mutations were detected also: T3540T, N3542N and T3552T. Analysis of lipid profiles of R3531C families showed, as with the R3500Q mutation, variable e xpression of the phenotype, modulated by environmental and other genetic fa ctors. Both mutations tend to produce lower plasma levels of LDL in affecte d subjects than do defects of the LDL receptor (familial hypercholesterolem ia, FH). This study shows that the Cys3531 LDL particles are not only defec tive at binding to the LDL receptor, as determined by two separate methods, but that in all cases they accumulate preferentially compared to the norma l allotype.