Millions Of Us Carry A Genetic Variant That Raises The Risk Of 'Implosive' Cell Death

Cells die all the time in our bodies; many without much fanfare. Others under duress of an infection self-implode, their disintegrated remains triggering the immune system into a state of heightened vigilance.

While usually tightly controlled, these processes of programmed cell death can come unstuck, causing cancer if cells don't die or unleashing too much inflammation if cells go boom more often than they should.

Recently, a team of researchers identified a genetic misstep that takes the cellular brakes off necroptosis – the ferocious type of programmed cell death that usually alerts the immune system to the presence of invaders, but can trigger an excessive inflammatory response if uncontrolled.

Now, in their latest study, the researchers estimate that this genetic variant, a single-base change in the gene encoding a protein called MLKL, can be found in up to 3 percent of people.

The researchers are yet to associate this MLKL gene variant with any one particular disease, though after characterizing its effects in cell cultures and animal models, they are confident it could increase people's risk of inflammatory diseases such as diabetes when combined with other genetic and environmental factors.

"For most of us, MLKL will stop when the body tells it to stop, but 2 to 3 percent of people have a form of MLKL that is less responsive to stop signals," explains Sarah Garnish, a cell biologist at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, who led the latest study.

​

"While 2 to 3 percent doesn't seem like much, when you consider the global population, this adds up to many millions of people carrying a copy of this gene variant."

The genetic variant is dubbed S132P for the substitution of serine with a proline molecule 132 amino acids along the MLKL protein.

In their earlier work, the team of researchers, led by WEHI cell biologist Joanne Hildebrand, identified S132P as the third most common human missense variant in MLKL. They also showed it steadily accumulates in cell membranes until those overloaded cells burst open, imploding with inflammatory molecules called cytokines.

​

In this study, the researchers revisited a global database of genome sequencing data to find S132P variants are thus far absent in people with East Asian ancestry; rare in African and Latino populations; and more common in individuals of Ashkenazi Jewish ancestry.

They also identified two carriers in an Australian registry of people with immune-related disorders, but wanted to better understand how S132P impacts inflammatory responses before jumping to any conclusions.

Lab experiments revealed how S132P promotes the build-up of the MLKL protein in cell membranes, enhancing necroptosis. Cells with the variant were also able to override chemical instructions to block MLKL activity, retaining their ability to self-detonate.

Moreover, mice engineered to carry two irregular copies of MLKL akin to the human variant showed disrupted immune responses: their pathogen-defense systems were impaired by widespread deficiencies in immune cells, with precursors to those cells showing an "enhanced propensity for cell death" when stressed.

Most humans don't carry two irregular copies of MLKL and mice in the study that possessed just one copy did not show the same risk of necroptosis. So this doesn't necessarily mean people with the mutation are doomed to ill health.

Something is clearly going on, but there's a lot more work to do yet to understand how genetic quirks in MLKL might possibly contribute to inflammatory conditions in humans.

Source