An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)

Familial hypercholesterolemia (FH) is caused by a defect in the function of the low density lipoprotein (LDL) receptor and inherited in an autosomal, codominant way. In this study we present a 13-year-old girl, compound heter ozygote for the LDL receptor mutations C240F and Y167X. Fibroblasts from th e patient showed very low cholesterol esterification rate, LDL uptake. and degradation compared to normal fibroblasts ( < 2%, 8%, and < 2%, respective ly). The C240F mutant was expressed in LDL receptor deficient CHOldlA7 cell s, Analysis of cell extracts by immunoblotting demonstrated delayed process ing of the mutated LDL receptor, which was accumulated as a precursor prote in of normal size. A high molecular weight form of the receptor was also de tectable in these cells, which probably reflects cross-linking through the unpaired cysteine residue in the binding domain, Cells expressing the C240F mutant protein were unable to mediate uptake and degradation of LDL. The t wo siblings of the index case also carried the C240F mutation, but surprisi ngly one of them (a 17-year-old brother showed no signs of hypercholesterol emia. This observation is consistent with the view that there may be choles terol lowering mechanisms that can be activated, perhaps by mutations in kn own or hitherto unknown genes.