Novel Homozygous Nonsense Mutation in Glucagon-like Peptide-2 Receptor Gene Resulting in Severe Human Illness

Glucagon-like peptide-2 (GLP2) acts on the GLP2 receptor (GLP2R) and plays a role in intestinal growth and adaptation. The endogenous actions of GLP2R do not have an established association with human disease, although mouse-knockout models in a stressed state show enhanced susceptibility to small bowel injury, increased morbidity, mortality, and abnormal host-bacterial interactions. We report an 11-month-old female with multiple intensive care unit admissions for severe metabolic acidosis due to profuse nonbloody diarrhea in the context of various infections. She had normal growth, lab testing, and stooling patterns between illnesses. Trio-whole genome sequencing revealed homozygous nonsense variants resulting in nonfunctional GLP2R. This is the first known human documented with a GLP2R-deficient phenotype, resulting in clinical illness, which correlates with the findings in the GLP2R mouse knockout model and furthers our understanding of GLP2R and the action of teduglutide, a GLP2 analog used for the treatment of short bowel syndrome.