Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism.
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.
Senée
Valérie
V
Institut Pasteur, Génétique des Maladies Infectieuses et Autoimmunes, 75015 Paris, France.
Chelala
Claude
C
Duchatelet
Sabine
S
Feng
Daorong
D
Blanc
Hervé
H
Cossec
Jack-Christophe
JC
Charon
Céline
C
Nicolino
Marc
M
Boileau
Pascal
P
Cavener
Douglas R
DR
Bougnères
Pierre
P
Taha
Doris
D
Julier
Cécile
C
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*
D004268:DNA-Binding Proteins; C512851:GLIS3 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors