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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 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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Figure 1: Linkage mapping and fine mapping in the three NDH families.
Figure 2: Identification and characterization of mutations in NDH families.
Figure 3: Expression of GLIS3 in human tissues.
Figure 4: Expression of Glis3 in mouse tissues.

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  1. Taha, D., Barbar, M., Kanaan, H. & Williamson Balfe, J. Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome? Am. J. Med. Genet. A 122, 269–273 (2003).

    Article  Google Scholar 

  2. Kim, Y.S., Nakanishi, G., Lewandoski, M. & Jetten, A.M. GLIS3, a novel member of the GLIS subfamily of Kruppel-like zinc finger proteins with repressor and activation functions. Nucleic Acids Res. 31, 5513–5525 (2003).

    Article  CAS  Google Scholar 

  3. Kanai, Y. & Hediger, M.A. Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360, 467–471 (1992).

    Article  CAS  Google Scholar 

  4. Peghini, P., Janzen, J. & Stoffel, W. Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration. EMBO J. 16, 3822–3832 (1997).

    Article  CAS  Google Scholar 

  5. Stoffers, D.A., Zinkin, N.T., Stanojevic, V., Clarke, W.L. & Habener, J.F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet. 15, 106–110 (1997).

    Article  CAS  Google Scholar 

  6. Sellick, G.S. et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat. Genet. 36, 1301–1305 (2004).

    Article  CAS  Google Scholar 

  7. Raeder, H. et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat. Genet. 38, 54–62 (2006).

    Article  CAS  Google Scholar 

  8. Katsushima, H., Kii, T., Soma, K., Ohyanagi, K. & Niikawa, N. Primary congenital glaucoma in a patient with trisomy 2q (q33-qter) and monosomy 9p(p24-pter). Case report. Arch. Ophthalmol. 105, 323–324 (1987).

    Article  CAS  Google Scholar 

  9. Verbraak, F.D. et al. Congenital glaucoma in a child with partial 1q duplication and 9p deletion. Ophthalmic Paediatr. Genet. 13, 165–170 (1992).

    Article  CAS  Google Scholar 

  10. Cohn, A.C. et al. Chromosomal abnormalities and glaucoma: a case of congenital glaucoma with trisomy 8q22-qter/ monosomy 9p23-pter. Ophthalmic Genet. 26, 45–53 (2005).

    Article  Google Scholar 

  11. Park, S.M. & Chatterjee, V.K. Genetics of congenital hypothyroidism. J. Med. Genet. 42, 379–389 (2005).

    Article  CAS  Google Scholar 

  12. Kim, Y.S. et al. Identification of Glis1, a novel Gli-related, Kruppel-like zinc finger protein containing transactivation and repressor functions. J. Biol. Chem. 277, 30901–30913 (2002).

    Article  CAS  Google Scholar 

  13. Zhang, F. et al. Characterization of Glis2, a novel gene encoding a Gli-related, Kruppel-like transcription factor with transactivation and repressor functions. Roles in kidney development and neurogenesis. J. Biol. Chem. 277, 10139–10149 (2002).

    Article  CAS  Google Scholar 

  14. Haumaitre, C. et al. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc. Natl. Acad. Sci. USA 102, 1490–1495 (2005).

    Article  CAS  Google Scholar 

  15. Villavicencio, E.H., Walterhouse, D.O. & Iannaccone, P.M. The sonic hedgehog-patched-gli pathway in human development and disease. Am. J. Hum. Genet. 67, 1047–1054 (2000).

    Article  CAS  Google Scholar 

  16. Lees, C., Howie, S., Sartor, R.B. & Satsangi, J. The hedgehog signaling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease. Gastroenterology 129, 1696–1710 (2005).

    Article  CAS  Google Scholar 

  17. Hebrok, M. Hedgehog signaling in pancreas development. Mech. Dev. 120, 45–57 (2003).

    Article  CAS  Google Scholar 

  18. Takahashi, M., Matsuda, F., Margetic, N. & Lathrop, M. Automated identification of single nucleotide polymorphisms from sequencing data. J. Bioinform. Comput. Biol. 1, 253–265 (2003).

    Article  CAS  Google Scholar 

  19. Hara, M. et al. Transgenic mice with green fluorescent protein-labeled pancreatic beta-cells. Am. J. Physiol. Endocrinol. Metab. 284, E177–E183 (2003).

    Article  CAS  Google Scholar 

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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.

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Correspondence to Cécile Julier.

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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)

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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).

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