Abstract
Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in EDEM2, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of Edem2 in rat RIN-m β-cells resulted in a decrease in insulin genes Ins1 to 67.9% (p = 0.006) and Ins2 to 16.8% (p < 0.001) and reduced insulin secretion by 60.4% (p = 0.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including Glut2 and Pxd1, with mRNA suppression to 54% (p < 0.001) and 85.7% (p = 0.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe EDEM2 as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of β-cell genes involved in the glucose‐stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgments
We thank our laboratory staff: Martin J. Larsen for performing the sequencing alignment, Jette Møller, Trine Jørgensen, and Flemming Bergholdt for performing the laboratory work.
Funding
This study was funded by The Research Fund, Region of Southern Denmark; The University of Southern Denmark, and King Abdullah International Research Centre.
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KB, HC, and MB were involved in planning and supervising the project. HC, and KH collected and provided the clinical data. YA and KB designed the experiments. YA performed the experiments. YA and KB analyzed the data. YA drafted the manuscript. All authors discussed the results and contributed to the final manuscript.
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Yazeid Alhaidan declares that he has no conflict of interest. Henrik Thybo Christesen declares that he has no conflict of interest. Kurt Højlund declares that he has no conflict of interest. Mohammed A. Al Balwi declares that he has no conflict of interest. Klaus Brusgaard declares that he has no conflict of interest.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the regional ethical committee of southern Denmark (sagnr. S-VF-20040235).
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Communicated by Stefan Hohmann.
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Alhaidan, Y., Christesen, H.T., Højlund, K. et al. A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion. Mol Genet Genomics 295, 1253–1262 (2020). https://doi.org/10.1007/s00438-020-01695-5
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DOI: https://doi.org/10.1007/s00438-020-01695-5