ANALYSIS OF LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE-MUTATIONS AND MICROSATELLITE HAPLOTYPES IN GREEK FH HETEROZYGOUS CHILDREN - 6 INDEPENDENTANCESTORS ACCOUNT FOR 60-PERCENT OF PROBANDS

This study reports the characterization of 60% of low density lipoprot ein receptor (LDLR) gene mutations in 150 unrelated Greek familial hyp ercholesterolaemia (FH) heterozygous children by the analysis of six L DLR gene mutations. The linkage disequilibrium of two polymorphic micr osatellites (D19S394 and D19S221) flanking the LDLR gene on chromosome 19 to the four most common mutations strongly suggests that each muta tion is identical-by-descent in the probands included in this study (t his is also supported by the geographical distribution of FH families with these mutations throughout Greece) and permits an estimation of t he number of generations from a common ancestor for each mutation. The characterization of 60% of LDLR mutations in a representative sample of Greek FH heterozygotes provides a basis for the diagnosis of FH thr ough DNA analysis in Greece, by using single-strand conformation polym orphism analysis followed by allele-specific oligonucleotide hybridiza tion (exon 6 mutations) or restriction endonuclease analysis (C152R, V 408M). A rapid diagnostic assay positive for the mutation has been dev eloped for the most common mutation, G528D. The application of simple DNA diagnostic assays for LDLR mutation analysis are appropriate for t he early identification of FH heterozygotes in Greece and are useful f or the primary prevention of coronary artery disease.