A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion

Yazeid Alhaidan*, Henrik Thybo Christesen, Kurt Højlund, Mohammed A. Al Balwi, Klaus Brusgaard

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalMolecular Genetics and Genomics
Volume295
Issue number5
Pages (from-to)1253-1262
ISSN1617-4615
DOIs
Publication statusPublished - 1. Sep 2020

Keywords

  • Genomics
  • GSIS pathway
  • Inborn errors of metabolism
  • Monogenic diabetes

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