A specific genetic mutation in the AGR2 gene is linked to a severe form of intestinal inflammation in infants, which results in the loss of mucus-producing cells and key mucus proteins, along with...
Mechanism
Synthesis from 1 study
A broken gene makes a faulty protein that can't help build the gut's protective mucus layer or fix internal cellular stress. This causes the mucus-producing cells to die off, leaving the gut lining exposed to bacteria, which triggers severe inflammation from infancy.
Most probable mechanism
A faulty protein caused by a genetic mutation can't help fold a key mucus component properly, which clogs up the cell's internal factory, causing it to shut down and die. Without these cells, no protective mucus is made, letting gut bacteria touch the lining and trigger severe inflammation from birth.
A missense variant in AGR2 reduces its ability to bind and assist in the proper folding of the MUC2 precursor protein in the endoplasmic reticulum.
Misfolded MUC2 accumulates in the endoplasmic reticulum, overwhelming its protein-folding capacity and triggering persistent endoplasmic reticulum stress.
The mutant AGR2 protein also fails to resolve endoplasmic reticulum stress independently of mucin folding, further impairing cellular homeostasis.
Sustained endoplasmic reticulum stress activates apoptotic pathways specifically in goblet cells, which are highly sensitive to proteostatic disruption.
Goblet cell apoptosis results in near-complete depletion of these cells, eliminating production of MUC2, MUC5AC, and MUC6 mucins and destroying the protective mucus barrier.
Loss of the mucus barrier allows direct contact between gut microbiota and the intestinal epithelium, initiating chronic inflammation.
Evidence from Studies
Supporting (1)
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Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease
Contradicting (0)
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