title: Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism.
abstract: We recently described a new neonatal diabetes syndrome associated with congenital hypothyroidism, congenital glaucoma, hepatic fibrosis and polycystic kidneys. Here, we show that this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor. In the original family, we identified a frameshift mutation predicted to result in a truncated protein. In two other families with an incomplete syndrome, we found that affected individuals harbor deletions affecting the 11 or 12 5'-most exons of the gene. The absence of a major transcript in the pancreas and thyroid (deletions from both families) and an eye-specific transcript (deletion from one family), together with residual expression of some GLIS3 transcripts, seems to explain the incomplete clinical manifestations in these individuals. GLIS3 is expressed in the pancreas from early developmental stages, with greater expression in beta cells than in other pancreatic tissues. These results demonstrate a major role for GLIS3 in the development of pancreatic beta cells and the thyroid, eye, liver and kidney.
authors.affiliation: Institut Pasteur, Génétique des Maladies Infectieuses et Autoimmunes, 75015 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Senée
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.forename: Sabine
authors.initials: S
authors.lastname: Duchatelet
authors.forename: Daorong
authors.initials: D
authors.lastname: Feng
authors.forename: Hervé
authors.initials: H
authors.lastname: Blanc
authors.forename: Jack-Christophe
authors.initials: JC
authors.lastname: Cossec
authors.forename: Céline
authors.initials: C
authors.lastname: Charon
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
authors.forename: Pascal
authors.initials: P
authors.lastname: Boileau
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cavener
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougnères
authors.forename: Doris
authors.initials: D
authors.lastname: Taha
authors.forename: Cécile
authors.initials: C
authors.lastname: Julier
mesh_terms: D000483:Alleles; D000818:Animals; D003409:Congenital Hypothyroidism / Q000235:genetics*; D004268:DNA-Binding Proteins; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C512851:GLIS3 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors