Novel functional APOB mutations outside LDL-binding region causing familial hypercholesterolaemia

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Familial hypercholesterolaemia (FH) is characterized by increased circulating low-density lipoprotein (LDL) cholesterol leading to premature atherosclerosis and coronary heart disease. Although FH is usually caused by mutations inLDLR, mutations inAPOBandPCSK9also cause FH but only a few mutations have been reported, APOB p.R3527Q being the most common. However, 30-80% of clinical FH patients do not present an identifiable mutation in any of the described genes. To identify the genetic cause of the hypercholesterolaemia in 65 patients without mutations inLDLR,PCSK9or in fragments of exon 26 and 29 ofAPOBcurrently analysed, we performed whole sequencing ofAPOBby pyrosequencing. A total of 10 putative mutations inAPOBwere identified. Flow cytometry with fluorescently labelled LDL from patients and relatives showed that p.Arg1164Thr (exon 22) and p.Gln4494del (exon 29) presented a 40% decrease in internalization in lymphocytes and HepG2 cells, very similar to APOB3527. The proliferation assays with U937 cells showed reduced growth for both cases. The variant p.Tyr1247Cys was found to be neutral and other three alterations were considered polymorphisms. Our results emphasize the need to study the wholeAPOBin routine protocols to improve patient identification and cardiovascular risk assessment.

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