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ABSTRACT 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 β cells than in other pancreatic tissues. These results demonstrate a major role for GLIS3 in the development of pancreatic β cells and the thyroid, eye, liver and kidney.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS MUTATIONS AND VARIANTS OF _ONECUT1_ IN DIABETES Article 18 October 2021 NOVEL VARIANTS IN THE STEM CELL NICHE FACTOR WNT2B DEFINE THE DISEASE

PHENOTYPE AS A CONGENITAL ENTEROPATHY WITH OCULAR DYSGENESIS Article Open access 01 February 2021 HAPLOINSUFFICIENCY OF _PRR12_ CAUSES A SPECTRUM OF NEURODEVELOPMENTAL, EYE, AND MULTISYSTEM

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Google Scholar  Download references ACKNOWLEDGEMENTS We thank F. Badghaish for contacting and providing detailed clinical information on family NDH2, and we thank the families for their kind

participation to this study. We are grateful to M. Pontoglio for discussions and critical reading of the manuscript. We thank P. Ghandil and S. Blanchard for their technical contributions.

This work was funded in part by a joined Juvenile Diabetes Research Foundation (JDRF)/INSERM/Fondation pour la Recherche Médicale (FRM) grant to C.J. and by a US National Institutes of

Health (NIH) grant (NIDDK62049) to D.R.C. We thank the Hospices Civils de Lyon for their support. AUTHOR INFORMATION Author notes * Valérie Senée, Claude Chelala and Sabine Duchatelet: These

authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Institut Pasteur, Génétique des Maladies Infectieuses et Autoimmunes, Paris, 75015, France Valérie Senée, Claude

Chelala, Sabine Duchatelet, Hervé Blanc, Jack-Christophe Cossec & Cécile Julier * Institut National de la Santé et de la Recherche Médicale (INSERM) U730, Paris, 75015, France Valérie

Senée, Claude Chelala, Sabine Duchatelet, Hervé Blanc, Jack-Christophe Cossec & Cécile Julier * Department of Biology, Pennsylvania State University, University Park, Pennsylvania,

16802, USA Daorong Feng & Douglas R Cavener * Centre National de Génotypage, Evry, 91057, France Céline Charon * Département d'Endocrinologie Pédiatrique, Hôpital Debrousse, Lyon,

69005, France Marc Nicolino * INSERM U449, Lyon, 69005, France Marc Nicolino * Département d'Endocrinologie Pédiatrique, Hôpital Cochin-Saint Vincent de Paul, Paris, 75014, France

Pascal Boileau & Pierre Bougnères * INSERM U561, Paris, 75014, France Pascal Boileau & Pierre Bougnères * Division of Pediatric Endocrinology, King Faisal Specialist Hospital and

Research Center, Jeddah, 21499, Kingdom of Saudi Arabia Doris Taha Authors * Valérie Senée View author publications You can also search for this author inPubMed Google Scholar * Claude

Chelala View author publications You can also search for this author inPubMed Google Scholar * Sabine Duchatelet View author publications You can also search for this author inPubMed Google

Scholar * Daorong Feng View author publications You can also search for this author inPubMed Google Scholar * Hervé Blanc View author publications You can also search for this author

inPubMed Google Scholar * Jack-Christophe Cossec View author publications You can also search for this author inPubMed Google Scholar * Céline Charon View author publications You can also

search for this author inPubMed Google Scholar * Marc Nicolino View author publications You can also search for this author inPubMed Google Scholar * Pascal Boileau View author publications

You can also search for this author inPubMed Google Scholar * Douglas R Cavener View author publications You can also search for this author inPubMed Google Scholar * Pierre Bougnères View

author publications You can also search for this author inPubMed Google Scholar * Doris Taha View author publications You can also search for this author inPubMed Google Scholar * Cécile

Julier View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Cécile Julier. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIG. 1 Mutation in a patient from family NDH1. (PDF 36 kb) SUPPLEMENTARY FIG. 2 Human _GLIS3_ gene

structure: alternative transcripts and predicted proteins. (PDF 40 kb) SUPPLEMENTARY FIGURE 3 Facial features of patients NDH3-3 and NDH3-4 at ages 6 months and 2 years, respectively,

showing characteristic facial morphology. (PDF 82 kb) SUPPLEMENTARY TABLE 1 Biochemical characteristics of patients. (PDF 50 kb) SUPPLEMENTARY TABLE 2 Primer sequences and PCR assays. (PDF

106 kb) SUPPLEMENTARY TABLE 3 Exon-intron structure of the human _GLIS3_ gene. (PDF 63 kb) SUPPLEMENTARY NOTE (PDF 81 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Senée, V., Chelala, C., Duchatelet, S. _et al._ Mutations in _GLIS3_ are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. _Nat

Genet_ 38, 682–687 (2006). https://doi.org/10.1038/ng1802 Download citation * Received: 19 December 2005 * Accepted: 20 April 2006 * Published: 21 May 2006 * Issue Date: 01 June 2006 * DOI:

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