Millions of people carry a genetic variant that causes cells to "explosive death" unnecessarily!

Millions of people carry a genetic variant that causes cells to "explosive death" unnecessarily!

Researchers have discovered a genetic variation found in up to 3% of the world's population that increases the risk of inflammation through a mechanism called "explosive cell death."
This study may shed light on why some people are more likely to develop diseases such as inflammatory bowel disease or to experience severe reactions to bacterial infections such as salmonella.

Genetic genes may be the reason for your being a vegetarian or your inability to give up meat!
Every minute, millions of cells in our bodies die intentionally. Cell death is an essential process that protects our bodies from diseases by removing unwanted, damaged or dangerous cells, and preventing the spread of viruses, bacteria and even cancer.

Researchers say that although there are different types of cell death, “explosive cell death,” known as cell necrosis (or necrosis), is characterized by its ferocity, as cells essentially explode, triggering an alarm for other cells in the body to respond to the presence of invaders. But it can lead to an excessive inflammatory response if not controlled.

Recently, a team of researchers identified a genetic error that prevents cells from necrosis. Researchers estimate that this genetic variant, a single-base change in the gene that encodes a protein called MLKL, could be found in up to 3% of people.

Researchers say that MLKL is necessary to stimulate the death of dead cells, a natural process that protects the body from infection. But in 3% of the world's population this can go wrong and lead to tissue damage.

Researchers have not yet linked the MLKL gene to any specific disease, although after identifying its effects in cell cultures and animal models, the study, conducted by the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, says it could increase people's risk of infection. inflammatory diseases such as diabetes and gastritis, or more severe reactions to infections, when combined with other genetic and environmental factors.

“Every piece of information like this helps us make personalized medicine more realistic,” explained Dr. Sarah Garnish, a cell biologist at the Walter and Eliza Hall Center for Medical Research, who led the study. She added: “For most of us, the MLKL gene will turn off 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. Although 2 to 3 percent does not seem like a lot, when you consider the global population "This means millions of people who carry a copy of this altered gene."

The genetic variant is called S132P to replace serine (an organic compound) with a proline molecule 132 amino acids along the MLKL protein.

In their previous work, the team led by Joan Hildebrand, a cell biologist at the Walter and Eliza Hall Institute for Medical Research, identified S132P as the third most common human variant in MLKL. They also showed that it steadily accumulates in cell membranes until those overburdened cells burst, bursting with inflammatory molecules called cytokines.

In this study, researchers revisited a global database of genome sequence data to find that S132P variants are so far absent in people of East Asian descent, and rare in African and Latino populations; It is more common in individuals of Ashkenazi Jewish origin.

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

Laboratory experiments revealed how S132P promotes the accumulation of MLKL protein in cell membranes, promoting necrosis. Cells with the variant were also able to bypass chemical instructions to block MLKL activity, while retaining their ability to self-detonate.

Moreover, mice engineered to carry two dysregulated copies of MLKL similar to the human variant showed impaired immune responses: their pathogen defense systems were disrupted by widespread deficiencies in immune cells, with the precursors of those cells displaying an “enhanced propensity for cell death” when be compressed.

Most humans do not carry two dysregulated copies of MLKL, and mice in the study that only had one copy did not show the same risk of necrosis. So this does not necessarily mean that those with this mutation are doomed to ill health.

Clearly something is going on, but there is a lot of work that researchers have to do yet to understand how genetic quirks in MLKL might contribute to inflammatory conditions in humans. 

The study was published in the journal Nature Communications.
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