Gene mutation discovery ‘like winning the lottery’

What do a group of mice in a San Francisco laboratory and just a handful of French-Canadian families in Quebec have in common?

A rare genetic mutation that McMaster University researcher and professor of medicine Rick Austin said could act as a “proverbial Fountain of Youth.”

The gene Austin is talking about is called PCSK9-Q152H. It’s a mutation of the PCSK9 gene — which all people have.

The mutation, on the other hand, has only been found in just a few FrenchCanadian families in Quebec.

It was first written about in 2011, after it was discovered by top Montreal Clinical Research Institute endocrinologist Michel Chrétien, an emeritus professor at the University of Montreal.

Work by Montreal scientists found that those carrying the mutated gene are healthy well into their late 80s and mid-90s, they have low levels of LDLcholesterol (bad cholesterol) in their blood and their liver function was “completely normal.”

“It’s like winning the lottery,” said Austin. “You would never have predicted it in a million years.”

The mice however tie into a recent study, which was headed up by Austin, Chrétien and Paul Lebeau of McMaster University and published on Nov. 19 in the Journal of Clinical Investigation.

How the mutation works

Austin said PCSK9 circulates in the blood after it is secreted out of the liver.

But, it can come back and stick to the liver and the LDL receptors, causing them to break down — even more significantly if found in high volume.

And that’s not what people should want, said Austin. They should want to have lots of the LDL receptors to take in the bad cholesterol from the blood.

People that have high levels of LDL (low-density lipoprotein) cholesterol — or bad cholesterol — in their blood are more susceptible to heart disease, said Austin.

But with the mutation, the PCSK9

Q152H does not get secreted, said Austin. The body’s’ internal quality control system says “it doesn’t look right” and gets stuck in the cell.

Normally, it would build up in the endoplasmic reticulum (ER). The cell then attempts to get rid of it, but if it can’t it causes the cell to get “very sick.”

With PCSK9-Q152H, it’s “different,” said Austin, who saw the results in his lab.

It’s retained, it accumulates and it’s not being secreted — but there were no signs of stress on the cells of the liver.

The cells seemed to be OK and it was a “surprise” to the team of researchers.

‘Absolutely fascinating ’

That first clue took Austin on research sabbatical to work with a team at Amgen Inc. in San Francisco, California in 2017. While there, his team “over-expressed” PCSK9-Q152H in mice, who don’t have PCSK9. The idea was that if they gave the mice the gene mutation, they’d look at their liver to see what would happen. Again, it didn’t cause ER stress. The livers seemed to be fine, said Austin, through measuring liver health and liver functions. The gene mutation also increases in liver cells important “ER chaperones” that have been shown to protect from liver injury and disease, said Austin.

“If we tried to cause liver damage in those mice, they were protected, said Austin.

It was the exact same effect Chrétien had seen in the French-Canadian families.

With the results of the study, Austin said researchers have found what may be the “Fountain of Youth.” And they’re hoping to work on ways to mirror the mutation — which the lucky few had.

The team is hoping to come up with a gene therapy approach that could offer an “innovative” treatment for and protection from a number of diseases that lead to early death. That includes liver cancer and cardiovascular disease, stated Chrétien in a release.