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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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.
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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)
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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). https://doi.org/10.1038/ng1802
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DOI: https://doi.org/10.1038/ng1802
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