An Activating STAT3 Mutation Causes Neonatal Diabetes Through Premature Induction of Pancreatic Differentiation

Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus that was presumed to result from beta-cell autoimmunity. We investigated an alternative hypothesis and analyzed the effect of STAT3 mutation on pancreatic development using patient-derived iPS cells differentiated into pancreatic progenitors. Early pancreatic endoderm developed similarly in STAT3K392R cells and healthy controls, but in later differentiation NEUROG3 expression was prematurely upregulated in STAT3K392R cells together with markedly increased INS and GCG expression. RNA-seq showed robust upregulation of NEUROG3 downstream targets. Correction of the STAT3 mutation with CRISPR/Cas9 resulted in complete reversal of the disease phenotype.