Rare Mutation in the PCSK9 Gene Confers Long Healthy Life – MedicalResearch.com

Posted: November 23, 2020 at 4:59 am

MedicalResearch.com Interview with:

Richard C. Austin, PhDProfessor and Career Investigator of the Heart and Stroke Foundation of OntarioAmgen Canada Research Chair in NephrologyMcMaster University and St. Josephs HealthcareHamilton, Ontario, Canada

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: A previous study published in 2011 by my collaborator, Dr. Michel Chretien at the IRCM, identified a rare mutation in the PCSK9, termed Q152H. Individuals harboring this mutation demonstrated dramatic reductions in their LDL cholesterol levels and had a significantly lower risk of CVD. Furthermore, individuals harboring the Q152H mutation showed increases in longevity with no evidence of other diseases such as liver disease, cancer and chronic kidney disease.This Q152H mutation was unique with only 4 families in Quebec shown to harbor this genetic variant.

In terms of its effect on PCSK9 expression/activity, themutation at Q152H was precisely at the cleavage site in PCSK9 necessary for its activation. As a result, the Q152H mutation fails to be cleaved and activated, thereby blocking its secretion into the circulation. This is why the Q152H mutation is considered a loss-of-function PCSK9 mutant. Given our labs interest in endoplasmic reticulum (ER) stress and ER storage diseases, we began to collaborate with Drs. Chretien and Seidah at the IRCM to investigate whether this Q152H mutant, when overexpressed in liver cells, would cause ER stress and liver cell injury. This was based on the findings that the Q152H mutant does not undergo autocatalytic cleavage and itssubsequent secretion from liver cells.

It is well known in the literature that the accumulation of misfolded or inactive proteins in the ER gives rise to ER stress and cell injury/dysfunction. As a result, we initially showed to our surprise that overexpression of the Q152H mutant in liver cells failed to cause ER stress BUT increased the protein levels of several important ER chaperones, GRP78 and GRP94, known to PROTECT against liver cell injury/dysfunction. As part of our JCI study, we furthered these studies to examine the effect of the Q152H mutant when overexpressed in the livers of mice. This is where we demonstrated that the Q152H mutation showed protection against ER stress-induced liver injury/dysfunction.

MedicalResearch.com: What are the main findings? How is this gene variant related to the PCSK9 inhibitor evolocumab (Repatha)?

1. That the Q152H variant is considered a loss-of-function PCSK9 variant that protects against CVD by lowering LDL cholesterol levels. The reason it is a loss-of-function variant is because the protein fails to be secreted out of liver cells because it is retained in the ER of hepatocytes.

In terms of its relation to evolocumab, there are some major differences. Evolocumab is a fully human monoclonal antibody against PCSK9 that can bind to circulating PCSK9 and block its ability to bind to the LDL receptor on the surface of the liver. As a result, the levels and half life of the LDL receptor increases on the surface of hepatocytes, thereby increasing the uptake of LDL cholesterol. You could say that evolocumab acts like a loss-of-function PCSK9 variant. As indicated above, the Q152H variant blocks the autocatalytic cleavage of PCSK9 and its secretion from the ER of hepatocytes. As a result, the Q152H PCSK9 protein is retained in the ER of hepatocytes and fails to be secreted into the blood.

MedicalResearch.com: What should readers take away from your report?

Response: That mutations in the PCSK9 gene that affect its activation may act to protect against several human diseases and may contribute to increaselongevity and good health. Therefore, gene therapy approaches or new medicines that block the secretion of PCSK9 protein from the liver may have multiple beneficial health effects.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: We recommend that future research will allow us to determine whether gene therapy to express the Q152H variant or small molecule inhibitors of PCSK9 activation in the liver are novel approaches aimed at protecting against BOTH CVD and liver disease. WE are now in the process of generating a Q152H knockin mouse (using CRISPR/Cas9) to better understand the health benefits of the Q152H variant. This unique mouse model will allow us to perform a number of novel studies aimed at understanding the role of the Q152H variant in tissues/organs that are know to express PCSK9, such as liver, small intestine, kidney and brain.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: This study has utilized both clinical and biomedical approaches to better understand how a rare mutation in the PCSK9 gene can have a number of surprisingly protective effects on several different diseases.


Paul F. Lebeau, Hanny Wassef, Jae Hyun Byun, Khrystyna Platko, Brandon Ason, Simon Jackson, Joshua Dobroff, Susan Shetterly, William G. Richards, Ali A. Al-Hashimi, Kevin D. Won, Majambu Mbikay, Annik Prat, An Tang, Guillaume Par, Renata Pasqualini, Nabil G. Seidah, Wadih Arap, Michel Chretien, Richard C. Austin.The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury.Journal of Clinical Investigation, 2020; DOI:10.1172/JCI128650

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