title: An Activating Mutation inSTAT3Results 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 inSTAT3with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact ofSTAT3-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 inSTAT3and pancreatic β-cell dysfunction.
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Velayos
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Martínez
authors.affiliation: Pediatrics Endocrinology, Ramon y Cajal University Hospital, Madrid, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Alonso
authors.affiliation: Immunogenetics Research Laboratory, Department of Genetics, Physical Anthropology and Animal Physiology, BioCruces Health Research Institute, UPV-EHU, Leioa, Spain.
authors.forename: Koldo
authors.initials: K
authors.lastname: Garcia-Etxebarria
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: Anibal
authors.initials: A
authors.lastname: Aguayo
authors.affiliation: Pediatrics Endocrinology, Ramon y Cajal University Hospital, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Camarero
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Urrutia
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: Martínez de LaPiscina
authors.affiliation: Pediatrics Endocrinology, Ramon y Cajal University Hospital, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Barrio
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain luisantonio.castanogonzalez@osakidetza.eus izortze.santingomez@osakidetza.eus.
authors.forename: Izortze
authors.identifier: 0000-0003-1651-6776
authors.initials: I
authors.lastname: Santin
authors.affiliation: Endocrinology and Diabetes Research Group, Hospital Universitario Cruces, BioCruces Health Research Institute, CIBERDEM, CIBERER, UPV-EHU, Barakaldo, Spain luisantonio.castanogonzalez@osakidetza.eus izortze.santingomez@osakidetza.eus.
authors.forename: Luis
authors.initials: L
authors.lastname: Castaño
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D046729:Colitis, Collagenous / Q000150:complications; D003409:Congenital Hypothyroidism / Q000150:complications / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D007328:Insulin; D060850:LIM-Homeodomain Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1