Two 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, we have applied single strand conformation polymorphism (SSCP) analysis and solid-phase sequencing. We identified two novel pathogenic mutations accounting for one third of the FH in this patient sample. Six patients 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 found to have a G deletion at nucleotide 518 in exon 4, causing a translational frameshift and a stop codon, 518delG. We have developed two polymerase 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 carriers of these two mutations. Furthermore, haplotype analysis revealed that all E10X mutation carriers had the allele determined by TaqI-, StuI+, AvaII+, NcoI- and all 518delG mutation carriers had the haplotype TaqI-, StuI+, AvaII-, NcoI+. This indicates that both mutations may have been inherited from common ancestors, respectively.