MUTATIONAL AND GENETIC-ORIGIN OF LDL RECEPTOR GENE-MUTATIONS DETECTEDIN BOTH BELGIAN AND DUTCH FAMILIAL HYPERCHOLESTEROLEMICS

DNA samples from 100 unrelated Belgian patients with familial hypercho lesterolemia (FH) were screened for the presence of specific low-densi ty lipoprotein receptor (LDLR) gene mutations, previously shown to be prevalent in related populations. Two point mutations, viz., P664L and a G to A splicing defect at position 1359-1, were detected in single Flemish-speaking families. A long-distance polymerase chain reaction ( PCR) assay, used to screen for the 4-kb and 2.5-kb deletions previousl y identified by Southern blot analyses in different parts of The Nethe rlands, revealed a 3-kb deletion in two Belgian patients. Comparison o f PCR product length showed that both Dutch deletions of exons 7-8 are identical to that found in Belgians, but different from the 2.5-kb de letion previously described in South Africans of mixed ancestry. The B elgian patients probably share a common ancestor, for each mutation id entified, with FH patients from The Netherlands, since all three mutat ions were associated with the same LDLR gene haplotype as described fo r the Dutch population. Analysis of the deletion junctions demonstrate d the role of a 31-bp repetitive sequence in the generation of large r earrangements involving exons 7 and 8 of the LDLR gene. The finding th at only 4 out of 100 analyzed Belgian hypercholesterolemics carry a kn own LDLR mutation that is prevalent in related populations suggests th at the Belgian FH population has its own spectrum of mutations.