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 21/2 years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation inEDEM2, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation ofEdem2in rat RIN-m beta-cells resulted in a decrease in insulin genesIns1to 67.9% (p = 0.006) andIns2to 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, includingGlut2andPxd1, 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 describeEDEM2as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of beta-cell genes involved in the glucose-stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.