Severe NEUROG3 mutation underlies pancreatic endocrine and exocrine insufficiency
Abstract Patients with NEUROG3 mutations suffer from diabetes mellitus due to pancreatic endocrinopathy and chronic malabsorptive diarrhea due to enteric endocrinopathy. We have identified a severe truncation mutation in NEUROG3 (P39PfsX38) that results in pancreatic exocrine insufficiency and significantly contributes to chronic malabsorptive diarrhea. We identified this novel phenotype by interrogating induced pluripotent stem cells from the NEUROG3-P39PfsX38 patient’s fibroblasts and an isogenic “wild-type” control cell line generated via CRISPR-Cas9 gene editing. We discovered that NEUROG3- P39PfsX38 lines failed to activate pancreatic progenitor and differentiated lineage markers, suggesting that the mutation may disrupt pancreatic organogenesis and could result in endocrine and exocrine dysfunction. Isogenic corrected cell lines differentiated into all pancreatic lineages. Clinical assessments concluded that the patient has exocrine pancreatic insufficiency. Treatment with pancreatic enzyme replacement therapy improved patient outcomes, including weight gain, fat absorption, and resolution of fat-soluble vitamin deficiency. These results expose a novel role for NEUROG3 in human pancreatic differentiation and illustrate how patient-specific stem cells can be used to interrogate disease etiology and affect patient care.