2 NOVEL MUTATIONS IN THE LDL RECEPTOR GENE - COMMON CAUSES OF FAMILIAL HYPERCHOLESTEROLEMIA IN A SPANISH POPULATION

In our investigation of the LDL receptor gene in 30 Spanish patients, who were clinically diagnosed as heterozygous FH and were unrelated, w e have applied single strand conformation polymorphism (SSCP) analysis and solid-phase sequencing. We identified two novel pathogenic mutati ons accounting for one third of the FH in this patient sample. Six pat ients were found to have a G to T substitution at nucleotide position 91 in exon 2 that results in a stop codon, E10X. Four patients were fo und to have a G deletion at nucleotide 518 in exon 4, causing a transl ational frameshift and a stop codon, 518delG. We have developed two po lymerase chain reaction (PCR) based assays to detect easily these two mutations in all the available family members. We found fourteen E10X mutation carriers and eighteen 518delG mutation carriers. There was no statistically significant difference in mean lipid levels between car riers of these two mutations. Furthermore, haplotype analysis revealed that all E10X mutation carriers bad the allele determined by TaqI-, S tuI+, AvaII+, NcoI- and all 518delG mutation carriers had the haplotyp e TaqI-, Stul+, AvaII-, NcoI+. This indicates that both mutations may have been inherited from common ancestors, respectively.