Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), an autosomal dominant inherited disorder associated with an increased risk of premature atherosclerosis. The aim of this study was to characterize the LDLR mutations in a group of 476 apparently non-related Spanish FH patients. The promoter region and the 18 exons with their flanking intron sequences of the LDLR gene were screened by PCR-SSCP analysis and DNA sequencing. In addition, we tested for the presence of the mutation p.R3500Q in the gene coding for apolipoprotein B-100 (apo B-100). We found 77 mutations previously described, and 39 novel mutations affecting the LDLR gene: 8 missense, 5 nonsense, 15 frameshift, 5 splicing, 4 in frame, one nucleotide change in the non-coding sequence of exon 1, and one silent variant. We have identified al least one of these LDLR gene mutations in 329 subjects (69%). Four patients were homozygous, 4 patients were compound heterozygous, 48 patients were found to carry two different sequence variants in the same allele and 4 patients carried three different sequence variants in the same allele. Additionally, 4 subjects were carriers of the p.R3500Q mutation in the apo B gene. All of these findings indicate that there is a broad spectrum of mutations and sequence variants in the LDLR gene causing FH in Spain.