A gene mutation that protects against disease

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Researchers at the Montreal Clinical Research Institute, Université de Montréal and McMaster University think they’ve found a fountain of youth — and it’s unique to a few French Canadian families.

Canadian scientists looking at a rare genetic mutation think they may have discovered the proverbial fountain of youth. But it’s not for everyone: so far, the mutation has only been found in a handful of French-Canadian families.

Called PCSK9Q152H, the mutation of the PCSK9 gene was initially thought to protect against cardiovascular diseases, but recent studies show it may protect against other human illnesses, mainly liver diseases. As a result, people with PCSK9Q152H could stay in good health and live longer.

Published today in the Journal of Clinical Investigation, the work was led by vascular biologists Richard Austin and Paul Lebeau of McMaster University and by Montreal Clinical Research Institute endocrinologist Michel Chrétien, an emeritus professor at Université de Montréal.

Gene therapy next?

Michel Chrétien

Credit: Amélie Philibert

“These are exciting findings — what we’ve found may represent a kind of fountain of youth,” said Austin, a medical professor and one of the senior authors of the study. “Now we want to see whether we can come up with a gene therapy approach to overexpress this specific mutant gene variant in the liver, and thereby offer an innovative treatment for a number of diseases that normally lead to early death.”

News of the PCSK9Q152H mutation was first published in 2011, after Chrétien, the current study’s lead clinical investigator, discovered it in a French-Canadian family. Mainly expressed in the liver, the mutated gene lowers a person’s 'bad' plasma LDL-cholesterol and prevents cardiovascular diseases. Chrétien and his IRCM colleague Hanny Wassef found it in two other large French-Canadian families, as well.

People carrying this gene mutation are surprisingly healthy well into their late 80s and mid-90s. In addition to their low plasma LDL-cholesterol and their low risk of cardiovascular diseases, their liver function is completely normal when measured through imaging and a complete medical evaluation, the Montreal scientists found.

Until now, however, the underlying mechanism by which the mutation represented a health benefit other than cardiovascular was a mystery.

A surprising protective effect

In the new study, the McMaster researchers show that overexpression of this gene variant in the livers of mice who don’t carry PCSK9Q152H had a surprising protective effect against injury and dysfunction of their liver. As well, overexpression led to a large reduction in their circulating PCSK9 levels — just as it does in people, decreasing individuals’ bad cholesterol and keeping them in good cardiovascular health.

“When we initiated these studies, we had speculated that introducing the mutant PCSK9Q152H protein into the liver of mice would cause liver injury or dysfunction,” Austin said.  But “to our amazement,” added Lebeau, “overexpression of the mutant gene variant in the livers of mice failed to cause stress in the cellular manufacturing and packaging system called the endoplasmic reticulum, or ER, and actually protected against ER stress-induced liver injury.”

In their laboratory, the McMaster scientists went on to show that the mutant gene variant acts as a unique co-chaperone protein to stabilize several well-known ER chaperones, namely GRP78 and GRP94, and to increase their protective activity against liver damage.

‘Particularly gratifying results’

“These results from Dr. Austin’s group are particularly gratifying since they experimentally explain that this gene mutation, known to lower cardiovascular accidents, also protects against liver injury and dysfunction, even in individuals who are in their late 80s and mid-90s,” said Dr. Chrétien, also an emeritus scientist at the Ottawa Hospital Research Institute.

“Furthermore, these findings should allow us to determine whether this unique mutation provides additional protection against liver diseases such as cancer, over and above its protective effect against cardiovascular accidents.”

About this study

"The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury," by Paul F. Lebeau et al, was published Nov. 19, 2020 in the Journal of Clinical Investigation. The study was funded in part by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada, the Fondation J-Louis Lévesque, the Richard and Edith Strauss Foundation, the Fondation Notre-Dame de Zeitoun, and the Aclon Foundation. 


In late February 2020, Montreal Clinical Research Institute scientists Michel Chrétien and Majambu Mbikay made headlines when they were invited to China to begin clinical trials to validate the therapeutic potential of isoquercetin on COVID-19 patients there.
Isoquertin is a plant-based chemical compound with notable antiviral properties.
The situation in China was quickly brought under control, however, and so the Montreal team no longer had a large number of COVID-19 patients needed to participate in their trials. To be conclusive, this type of study requires a large pool of patients at various stages of the disease.
As a result, the work was brought back to Canada, where the rate of progression of the virus remained high. After several months of waiting, the team obtained approval from Health Canada to begin their promising work in a valid and safe manner, in accordance with Canadian standards.
Vaccines will certainly help reduce the number of people who will get COVID-19 in the future. However, antivirals such as isoquicercetin, if proven effective against the disease, will remain essential to treat those who get it despite the availability of vaccines, the researchers believe.

About the IRCM

Founded in 1967, the Institut de recherches cliniques de Montréal (IRCM) / Montreal Clinical Research Institute is a non-profit organization that conducts fundamental and clinical biomedical research in addition to training high-level young scientists. With its cutting-edge technology facilities, the Institute brings together 33 research teams working in cancer, immunology, neuroscience, cardiovascular and metabolic diseases, systems biology and medicinal chemistry. The IRCM also operates a research clinic specialized in hypertension, cholesterol, diabetes and cystic fibrosis, as well as a research centre on rare and genetic diseases in adults. The IRCM is affiliated with Université de Montréal and associated with McGill University. Its clinic is affiliated with the Centre hospitalier de l’Université de Montréal (CHUM). The IRCM is supported by the Ministère de l’Économie, de la Science et de l’Innovation (Quebec Department of Economy, Science and Innovation).

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