Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low-density lipoprotein receptor (LDLR) gene. To date, there has not been a systematic survey of the frequency of gross mutations in the LDLR gene in the Spanish population. The objective of our study was to investigate large rearrangements in the Spanish FH population and the relation between the kind of large rearrangement and the phenotype in carrier families.
Materials and methods: The LDLR gene was screened to detect major rearrangements in a sample of 89 probands. Southern blot, long polymerase chain reaction (PCR), reverse transcription (RT) -PCR and DNA sequencing were used to detect and characterize the mutations.
Results: Five large rearrangements were found in six probands. Two mutations were due to duplications of internal regions of the gene, whereas the rest were caused by partial deletions, which eliminated the promoter region in two cases. The internal rearrangements, two duplications and one deletion, were apparently caused by recombination between ALU sequences and the study of their mRNA indicated that the reading frame was maintained. The analysis of the lipid profile between patients with similar characteristics (age, sex, body mass index, etc.) but carrying mutations that either eliminated the promoter region or produced internal rearrangements showed significant differences (total cholesterol: 366.6 +/- 81.8 vs. 304.6 +/- 25.1 P = 0.023, and LDL cholesterol: 317.7 +/- 65.1 vs. 249.2 +/- 27.4 P = 0.003).
Conclusions: The frequency of large mutations in a Spanish FH sample was close to 7% and at least four of the mutations found had not been described in other populations. Mutations that eliminate the promoter region originate more severe hypercholesterolemia than defective mutations, which suggests that the absence of the promoter region and transcription of the LDLR gene is worse compensated than the synthesis of a defective LDL receptor.