MUTATION SCREENING OF THE LDLR GENE AND APO-B GENE IN PATIENTS WITH APHENOTYPE OF FAMILIAL HYPERCHOLESTEROLEMIA AND NORMAL VALUES IN A FUNCTIONAL LDL RECEPTOR APOLIPOPROTEIN-B ASSAY

Mutations in the LDL receptor (LDLR) or the apolipoprotein B-100 genes causing familial hypercholesterolemia (FH) and familial defective apo lipoprotein B-100 (FDB), two of the most frequent inherited diseases, are the underlying genetic defects in a small proportion of patients s uffering from premature atherosclerotic heart disease. Consequently, s ecure diagnostic tools for these conditions allowing early preventive measures are needed. Since clinical and biochemical diagnosis often is inaccurate, assays analyzing patient LDLR function and LDL affinity h ave been established. These assays are, however, not able clearly to d ifferentiate between suspected FH/FDB samples and normal controls. To evaluate if this may be caused by other hitherto undescribed genetic d efects or to failure of the functional assays, we undertook denaturing gradient gel electrophoresis based mutation screening of the LDLR gen e and the codon 3456-3553 region of the apolipoprotein B gene in six F rench FH/FDB patients with normal outcomes on functional assays. In al l six patients, pathogenic LDLR mutations were found, including three previously undescribed mutations, suggesting that failure of the funct ional assays explains the normal results found in some phenotypic FH/F DB patients and illustrating the need for DNA based screening techniqu es for routine genetic diagnosis in FH/FDB. (C) Munksgaard, 1998.