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

Clinica Chimica Acta; International Journal of Clinical Chemistry
Thea Bismo StrømTrond P Leren

Abstract

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...Continue Reading

References

Jan 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·A SnidermanP O Kwiterovich
May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
May 1, 2004·Proceedings of the National Academy of Sciences of the United States of America·Kara N Maxwell, Jan L Breslow
Apr 9, 2005·Cellular and Molecular Life Sciences : CMLS·G SchonfeldP Yue
Jan 21, 2006·Arteriosclerosis, Thrombosis, and Vascular Biology·Knut Erik BergeTrond P Leren
Jan 27, 2006·European Journal of Clinical Investigation·P PariniM Rudling
Mar 24, 2006·The New England Journal of Medicine·Jonathan C CohenHelen H Hobbs
Mar 31, 2006·Human Molecular Genetics·Jamie CameronTrond P Leren
Nov 3, 2006·The Journal of Clinical Investigation·Thomas A LagaceJay D Horton
Dec 16, 2006·Arteriosclerosis, Thrombosis, and Vascular Biology·Tommaso FasanoPatrizia Tarugi
May 12, 2007·The Journal of Biological Chemistry·Timothy S FisherAyesha Sitlani
Feb 13, 2008·Journal of Internal Medicine·J CameronT P Leren
Aug 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Maria Frank-KamenetskyKevin Fitzgerald
Aug 20, 2008·Clinica Chimica Acta; International Journal of Clinical Chemistry·Trond P Leren, Knut Erik Berge
May 16, 2009·Proceedings of the National Academy of Sciences of the United States of America·Joyce C Y ChanSimon M Jackson

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Citations

Mar 1, 2012·Journal of Lipid Research·R HuijgenJ J P Kastelein
Feb 13, 2014·Clinica Chimica Acta; International Journal of Clinical Chemistry·Na-Qiong Wu, Jian-Jun Li
Nov 15, 2011·Biochemical and Biophysical Research Communications·Thea Bismo StrømTrond P Leren
Nov 15, 2011·Molecular Genetics and Metabolism·Kristian TvetenTrond P Leren
May 3, 2011·Biochemical and Biophysical Research Communications·Thea Bismo StrømTrond P Leren
Feb 6, 2017·Current Opinion in Lipidology·Jacqueline S Dron, Robert A Hegele
Oct 4, 2014·Arteriosclerosis, Thrombosis, and Vascular Biology·Yascara Grisel Luna SaavedraAlexis Baass
Jun 1, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Khadijeh MahboobniaAmirhossein Sahebkar

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