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

Abstract

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 with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of-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 and pancreatic β-cell dysfunction.

Suppression of STAT3 signaling promotes cellular reprogramming into insulin-producing cells induced by defined transcription factors

“…Our in vitro experiments also demonstrated that the activation of STAT3 signaling robustly inhibits the cellular reprogramming of mPAC cells into insulin-producing cells. These findings are consistent with the phenotypes of neonatal diabetes caused by activating mutations in STAT3 [ 22 , 29 ]. Saarimaki-Vire et al recently reported the activating mutation STAT3 K392R in a patient with neonatal diabetes, and an in vitro study using the patient-derived iPS cells demonstrated that aberrant STAT3 signaling caused premature endocrine differentiation through induced NEUROG3 expression [ 22 ].…”

“…In addition, STAT3 was shown to induce the cellular reprogramming of exocrine (acinar or ductal) cells into an endocrine cell fate through transient cytokine treatment [ 2 , 28 ]. On the other hand, activating mutations in human STAT3 have been reported to be linked to neonatal diabetes accompanied by β-cell failure [ 22 , 29 ], showing that the aberrant activation of STAT3 causes premature endocrine differentiation through the upregulation of NEUROG3 .…”

Partial growth hormone insensitivity and dysregulatory immune disease associated with de novo germline activating STAT3 mutations

“…However, short stature is a key clinical finding in these patients. To our knowledge, 15 out of 22 reported patients with available growth data (Flanagan et al, 2014; Haapaniemi et al, 2015; Milner et al, 2015; Sediva et al, 2017; Velayos et al, 2017; Weinreich et al, 2017) (~68%, including our patients) had growth impairment (Supplementary Table 4 and Supplementary Fig. 2) and our in vitro studies suggest a disruptive role of STAT3 GOF variants in the GH signaling pathway.…”

Role of the JAK2/STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications

“…The STAT3 signaling pathway participates in the development of insulin resistance in skeletal muscles and T2DM [ 23 ]. In addition, its abnormal activation possibly damages islet beta cells, which reduces insulin synthesis [ 24 ]. A recent study indicated that the JAK/STAT pathway participates in high glucose-induced HUVEC damage [ 18 ].…”