Patient iPSCs with NEUROG3 mutation reveal pancreatic insufficiency

Patients with NEUROGENIN3 mutations have enteric endocrinopathy and diabetes mellitus. We generated pluripotent stem cells from a patient's fibroblasts to investigate if gene editing restores endocrine differentiation. Corrected cell lines differentiated into all pancreatic lineages while native cell lines failed to activate pancreatic progenitor and lineage determination genes, suggesting that the mutation disrupts pancreatic organogenesis and results in endocrine and exocrine dysfunction. Clinical testing revealed the patient has exocrine pancreatic insufficiency. These results expose a novel role for NEUROGENIN3 in human pancreatic differentiation and illustrates how patient-specific stem cells can be used to interrogate disease etiology and affect patient care. Overall design: 14 samples were analyzed for bulk RNA sequencing. We sequenced two biological replicates for NGN3-NULL at stages 3, 4, and 5. We sequenced two biological replicates for NGN3-CORR at stages 4 & 5, and one biological replicate at stage 3. We used the H1 line as a control at stages 3, 4, and 5.