Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism

Valérie Senée^1, 2, 10, Claude Chelala^1, 2, 10, Sabine Duchatelet^1, 2, 10, Daorong Feng³, Hervé Blanc^1, 2, Jack-Christophe Cossec^1, 2, Céline Charon⁴, Marc Nicolino^5, 6, Pascal Boileau^7, 8, Douglas R Cavener³, Pierre Bougnères^7, 8, Doris Taha⁹ & Cécile Julier^1, 2

¹  Institut Pasteur, Génétique des Maladies Infectieuses et Autoimmunes, 75015 Paris, France.

²  Institut National de la Santé et de la Recherche Médicale (INSERM) U730, 75015 Paris, France.

³  Department of Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA.

⁴  Centre National de Génotypage, 91057 Evry, France.

⁵  Hôpital Debrousse, Département d'Endocrinologie Pédiatrique, 69005 Lyon, France.

⁶  INSERM U449, 69005 Lyon, France.

⁷  Hôpital Cochin-Saint Vincent de Paul, Département d'Endocrinologie Pédiatrique, 75014 Paris, France.

⁸  INSERM U561, 75014 Paris, France.

⁹  Division of Pediatric Endocrinology, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Kingdom of Saudi Arabia.

¹⁰  These authors contributed equally to this work.

We recently described a new neonatal diabetes syndrome associated with congenital hypothyroidism, congenital glaucoma, hepatic fibrosis and polycystic kidneys¹. Here, we show that this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor². 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 cells than in other pancreatic tissues. These results demonstrate a major role for GLIS3 in the development of pancreatic cells and the thyroid, eye, liver and kidney.

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