Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease

Area of Science:

• Gastroenterology
• Genetics
• Immunology

Background:

• The gastrointestinal epithelium maintains gut homeostasis, with mucins crucial for barrier function.
• Mucin 2 (MUC2) is a key gel-forming mucin produced by goblet cells.
• Anterior gradient 2 (AGR2) is vital for proper mucin processing.

Purpose of the Study:

• Investigate the genetic basis of severe infantile-onset inflammatory bowel disease in two siblings.
• Determine the role of AGR2 variants in intestinal barrier defects and endoplasmic reticulum (ER) stress.

Main Methods:

• Whole-genome sequencing to identify genetic variants.
• Histology and immunohistochemistry to analyze goblet cells and mucin expression.
• Co-immunoprecipitation and cell-based assays to assess AGR2-MUC2 binding and ER stress response.

Main Results:

• Siblings were homozygous for a missense variant in AGR2.
• Biopsies revealed reduced goblet cells, depleted mucins (MUC2, MUC5AC, MUC6), elevated AGR2, and increased ER stress.
• Mutant AGR2 exhibited impaired MUC2 binding and failed to alleviate ER stress.

Conclusions:

• The identified AGR2 missense variant is pathogenic, causing a Mendelian deficiency termed EAGLES.
• EAGLES leads to mucus barrier defects and ER stress, resulting in infantile-onset inflammatory bowel disease.
• This finding highlights AGR2's critical role in intestinal health.