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Background Epidemiological studies have shown that low levels of plasma high density lipoprotein (HDL) cholesterol are associated with increased risk of ischemic heart disease (IHD), but it appears that genetic forms of low HDL cholesterol levels, as opposed to lifestyle-induced low levels of HDL cholesterol, do not result in increased risk of IHD. Therefore, the etiology of reduced levels of plasma HDL cholesterol may represent a factor that should be considered in risk stratification with respect to primary prevention. Genes encoding proteins involved in HDL metabolism, such as the ATP-binding cassette transporter A1 (ABCA1) and apolipoprotein (apo) A-I genes, are candidate genes for harboring mutations that lead to low HDL cholesterol levels. Methods The ABCA1 and apoA-I genes in 56 Norwegian patients, with a mean HDL cholesterol level of 0.53 (± 0.15) mmol/l, were subjected to DNA sequencing. Results Several mutations were identified in the ABCA1 gene, and two mutations were identified in the apoA-I gene. A total of 18 patients (32%) were carriers of mutations considered to be pathogenic. Their mean HDL cholesterol level was 0.45 (± 0.15) mmol/l compared to 0.57 (± 0.14) mmol/l in noncarriers (p Conclusion Mutations in the genes encoding ABCA1 and apoA-I are common in Norwegians, with a markedly decreased HDL cholesterol level.

Background Familial hypercholesterolemia (FH) patients with the splice site mutation c.313+1, G>A in intron 3 of the low density lipoprotein receptor (LDLR) gene, present with a phenotype similar to that of FH patients in general. However, a mild phenotype would have been expected from the published data showing that the mutation only causes skipping of exon 3. Methods Epstein Barr virus-transformed lymphocytes from eight c.313+1, G>A heterozygotes and two c.313+1, G>A homozygotes were subjected to studies of the LDLR at the mRNA and protein levels. Results Mutation c.313+1, G>A not only causes skipping of exon 3, but also causes inclusion of intron 3. No functional LDLR was produced from the transcript with inclusion of intron 3. The transcript with skipping of exon 3 produced a receptor which had markedly reduced ability to internalize low density lipoprotein. Conclusion The findings that the mutation c.313+1, G>A in the LDLR gene also generates a mutant transcript with inclusion of intron 3, explains why the mutation c.313+1, G>A may result in a severe phenotype.

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.

Background: Familial LPL deficiency is a rare inborn error of metabolism caused by mutational change within the LPL gene, which leads to massive hypertriglyceridemia. Methods: The underlying molecular defect in a boy of Croatian descent was studied by SSCP analysis, DNA sequencing and finally confirmed by RFLP. Results: DNA analysis showed the child to be a homozygote and his parents heterozygotes for TGG→CGG change in codon 86 of the LPL gene, which leads to W86R amino acid substitution. DNA sequence analysis also showed a silent mutation in the third exon of father's DNA, V108V. Determination of some LPL gene polymorphisms showed the child and his parents to have HindIII/H+H+ and both S447 wild-type alleles, whereas for PvuII the parents had P+P− and the child P+P+ genotype. Conclusions: In this case, W86R mutation was the reason for the production of nonfunctional enzyme and consequently triacylglycerol (TG) exceeding 15 mmol/l. This implies the risk of frequent episodes of acute pancreatitis. Decreased LPL activity leads to elevated triacylglycerol levels and reduced HDL-cholesterol, both risk factors for the development of coronary artery disease. LPL genotyping especially of young patients with hypertriglyceridemia is therefore necessary and justifiable.