2 FOUNDER MUTATIONS IN THE LDL RECEPTOR GENE IN NORWEGIAN FAMILIAL HYPERCHOLESTEROLEMIA SUBJECTS

DNA from 20 unrelated familial hypercholesterolemia (FH) subjects were studied by analysis of single-strand conformation polymorphisms (SSCP) for mutations in exon 3 of the low density lipoprotein (LDL) receptor gene. Four different SSCP patterns were observed. The underlying mutations were characterized by DNA sequencing. One pattern represented the wild-type sequence. Another pattern represented a C-->G mutation (FH-Svartor) that changes codon 78 into the amber stop codon. The two other patterns represented heterozygosity and homozygosity, respectively, for a G-->A splice donor mutation (FH-Elverum) in intron 3. Based upon two PCR-based assays, the frequencies of FH-Svartor and FH-Elverum among 267 unrelated FH subjects, were 8% and 25%, respectively. FH Svartor was located on a chromosome with haplotype 3 in all five families where haplotype analysis were performed. FH Elverum was located on haplotype 2 in 16 out of 20 families. The two mutations must be considered founder mutations in the Norwegian population, and their existence will be clinically useful in diagnosing FH. The presence of two founder mutations together with previously published data on the prevalence of FH in Norway, indicate that FH may be a more common disease in Norway than previously thought.