An Activating Mutation in STAT3 Results in Neonatal Diabetes Through Reduced Insulin Synthesis

Diabetes. 2017 Apr;66(4):1022-1029. doi: 10.2337/db16-0867. Epub 2017 Jan 10.


Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for ∼20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in STAT3 with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of STAT3-activating mutations have not been characterized at the pancreatic β-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic β-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in STAT3 and pancreatic β-cell dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Chromatin Immunoprecipitation
  • Colitis, Collagenous / complications
  • Congenital Hypothyroidism / complications
  • Congenital Hypothyroidism / genetics*
  • Diabetes Mellitus / genetics*
  • Female
  • Humans
  • Infant, Newborn
  • Insulin / biosynthesis*
  • Insulin-Secreting Cells / metabolism*
  • LIM-Homeodomain Proteins / metabolism
  • Mutation
  • Mutation, Missense
  • Rats
  • Real-Time Polymerase Chain Reaction
  • STAT3 Transcription Factor / genetics*
  • Sequence Analysis, DNA
  • Transcription Factors / metabolism
  • Transfection


  • Insulin
  • LIM-Homeodomain Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, rat
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1

Supplementary concepts

  • Diabetes Mellitus, Neonatal, with Congenital Hypothyroidism