LOW-DENSITY-LIPOPROTEIN RECEPTOR MUTATIONS IN A SELECTED POPULATION OF INDIVIDUALS WITH MODERATE HYPERCHOLESTEROLEMIA

To evaluate mutations in the low density lipoprotein receptor (LDL-R) gene in moderate primary hypercholesterolemia, a combination of polyme rase chain reaction (PCR), single-strand conformation polymorphism (SS CP) and direct sequencing, was used to screen the LDL-R gene in a sele cted population of 82 unrelated individuals with moderate elevation of plasma LDL-C [mean 4.55 +/- 0.55 mmol/l (176.4 +/- 21.6 mg/dl)]. Four subjects (5%) were found to be heterozygotes for missense mutations i n the LDL-R gene. These mutations were located in four different exons (exons 6, 7 15 and 17) and all alters highly conserved residues of LD L-R protein. None of these mutations were detected in 79 normocholeste rolemic individuals. The mutation in exon 15 (T705I) was previously re ported in a compound heterozygote for familial hypercholesterolemia (F H). In the proband carrying the mutation in exon 17 (R793Q), an in viv o LDL turnover study was performed and it demonstrated a reduction of LDL catabolism. These findings demonstrate that mutations in the LDL-R may occur in primary moderate hypercholesterolemia. They also extend the concept that some FH patients may present with a mild phenotype. ( C) 1998 Elsevier Science Ireland Ltd.