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

作者：Saarimaki Vire Jonna; Balboa Diego; Russell Mark A; Saarikettu Juha; Kinnunen Matias; Keskitalo Salla; Malhi Amrinder; Valensisi Cristina; Andrus Colin; Eurola Solja; Grym Heli; Ustinov Jarkko; Wartiovaara Kirmo; Hawkins R David; Silvennoinen Olli; Varjosalo Markku; Morgan Noel G; Otonkoski Timo

来源：Cell Reports, 2017, 19(2): 281-294.

DOI：10.1016/j.celrep.2017.03.055

Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus associated with beta-cell autoimmunity. We have investigated the effect of an activating mutation, STAT3(K392R,) on pancreatic development using induced pluripotent stem cells (iPSCs) derived from a patient with neonatal diabetes and pancreatic hypoplasia. Early pancreatic endoderm differentiated similarly from STAT3(K392R) and healthy-control cells, but in later stages, NEUROG3 expressionwas upregulated prematurely in STAT3(K392R) cells together with insulin (INS) and glucagon (GCG). RNA sequencing (RNA-seq) showed robust NEUROG3 downstream targets upregulation. STAT3 mutation correction with CRISPR/Cas9 reversed completely the disease phenotype. STAT3(K392R) -activating properties were not explained fully by altered DNA-binding affinity or increased phosphorylation. Instead, reporter assays demonstrated NEUROG3 promoter activation by STAT3 in pancreatic cells. Furthermore, proteomic and immunocytochemical analyses revealed increased nuclear translocation of STAT3(K392R). Collectively, our results demonstrate that the STAT3(K392R) mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression.

• 出版日期2017-4-11