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Clin Chim Acta. 2010 Feb;411(3-4):229-33. doi: 10.1016/j.cca.2009.11.008. Epub 2009 Nov 13.

Loss-of-function mutation R46L in the PCSK9 gene has little impact on the levels of total serum cholesterol in familial hypercholesterolemia heterozygotes.

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Medical Genetics Laboratory, Department of Medical Genetics, Oslo University Hospital Rikshospitalet, Oslo, Norway.



Published data may suggest that the cholesterol-lowering effect of mutation R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene in familial hypercholesterolemia (FH) heterozygotes, is less pronounced than in normocholesterolemic subjects.


1130 unrelated subjects with molecularly defined FH were screened for mutation R46L in the PCSK9 gene and cell culture experiments were performed to study the effect of high concentrations of low density lipoprotein (LDL) on the binding of PCSK9 to the LDL receptor (LDLR).


2.7% of the subjects were carriers of the R46L mutation and they had a non-significant 6% lower value for total serum cholesterol than non-carriers. This reduction is lower than the 8-9% reduction in total serum cholesterol levels previously observed in normocholesterolemic subjects. Cell culture experiments showed that increasing concentrations of low density lipoprotein (LDL) in the media, decreased the amount of PCSK9 internalized and decreased the PCSK9-mediated degradation of the LDLR.


High levels of LDL, as seen in untreated FH heterozygotes, compete against wild-type PCSK9 for binding to the LDLR. Thus, in the presence of high LDL levels, wild-type-PCSK9, which has twice the binding affinity of R46L-PCSK9 to bind to the LDLR, may not be significantly more potent in degrading the LDLR than R46L-PCSK9. These data may suggest that targeting PCSK9 as monotherapy in FH heterozygotes, may not prove to be very effective.

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