Background: Characterization of the normally occurring mutations as the cause of hypocholesterolemia may increase our understanding of the normal lipid metabolism.
Methods: DNA from 93 unrelated hypocholesterolemic subjects with a mean (+/-SD) value for total serum cholesterol of 3.3 (+/-0.5) mmol/l) were subjected to DNA sequencing of the individual exons of the apolipoprotein B-100 (apoB-100) gene and of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene. The same analyses were also performed in 23 unrelated subjects with autosomal dominant hypercholesterolemia who had unusually low levels of total serum cholesterol.
Results: Of the 93 hypocholesterolemic subjects, 9 subjects (9.7%) were heterozygous for a truncating mutation in the apoB-100 gene and six subjects (6.5%) were heterozygous for a loss-of-function mutation in the PCSK9 gene. Of the 23 subjects with autosomal dominant hypercholesterolemia, four subjects (17.4%) were heterozygous for mutations in the apoB-100 gene.
Conclusion: Truncating mutations in the apoB-100 gene are slightly more common as the cause of hypocholesterolemia compared to loss-of-function mutations in the PCSK9 gene. It appears that mutations in the apoB-100 gene may completely normalize the lipid profile in subjects with autosomal dominant hypercholesterolemia, whereas loss-of-function mutations in the PCSK9 gene do not have a sufficient cholesterol-lowering capacity.