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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620345
Title:
An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation.
Authors:
Saarimäki-Vire, J.; Balboa, D.; Russell, M. A.; Saarikettu, J.; Kinnunen, M.; Keskitalo, S.; Malhi, A.; Valensisi, C.; Andrus, C.; Eurola, S.; Grym, H.; Ustinov, J.; Wartiovaara, K.; Hawkins, R. D.; Silvennoinen, O.; Varjosalo, M.; Morgan, Noel; Otonkoski, T.
Abstract:
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 expression was 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.
Citation:
An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation. 2017, 19 (2):281-294 Cell Rep
Publisher:
Cell Press
Journal:
Cell Reports
Issue Date:
11-Apr-2017
URI:
http://hdl.handle.net/11287/620345
DOI:
10.1016/j.celrep.2017.03.055
PubMed ID:
28402852
Additional Links:
https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(17)30416-3
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
2211-1247
Appears in Collections:
Honorary contracts publications; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorSaarimäki-Vire, J.en
dc.contributor.authorBalboa, D.en
dc.contributor.authorRussell, M. A.en
dc.contributor.authorSaarikettu, J.en
dc.contributor.authorKinnunen, M.en
dc.contributor.authorKeskitalo, S.en
dc.contributor.authorMalhi, A.en
dc.contributor.authorValensisi, C.en
dc.contributor.authorAndrus, C.en
dc.contributor.authorEurola, S.en
dc.contributor.authorGrym, H.en
dc.contributor.authorUstinov, J.en
dc.contributor.authorWartiovaara, K.en
dc.contributor.authorHawkins, R. D.en
dc.contributor.authorSilvennoinen, O.en
dc.contributor.authorVarjosalo, M.en
dc.contributor.authorMorgan, Noelen
dc.contributor.authorOtonkoski, T.en
dc.date.accessioned2017-05-26T11:31:33Z-
dc.date.available2017-05-26T11:31:33Z-
dc.date.issued2017-04-11-
dc.identifier.citationAn Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation. 2017, 19 (2):281-294 Cell Repen
dc.identifier.issn2211-1247-
dc.identifier.pmid28402852-
dc.identifier.doi10.1016/j.celrep.2017.03.055-
dc.identifier.urihttp://hdl.handle.net/11287/620345-
dc.description.abstractActivating 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 expression was 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.en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S2211-1247(17)30416-3en
dc.rightsArchived with thanks to Cell Reportsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleAn Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation.en
dc.typeJournal Articleen
dc.identifier.journalCell Reportsen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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