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.

单基因糖尿病是一种罕见的糖尿病，它是由单个基因的突变引起的。迄今为止，大多数病例在遗传上仍无法解释，这对准确的糖尿病治疗提出了挑战，从而导致了分子诊断。因此，对一名发病于2½岁且自身抗体呈阴性的糖尿病的苗条，非综合症的白人女孩进行了三重外显子组扫描。这位瘦弱的父亲从11岁开始患有糖尿病。EDEM2中一个新的杂合突变，c.1271G> A；p.Arg424His，在先证者和父亲中被发现。大鼠RIN- mβ细胞中Edem2的下调导致胰岛素基因Ins1降至67.9％（p  = 0.006）和Ins2降至16.8％（p <0.001），并将胰岛素分泌减少60.4％（p  = 0.0003）。实时PCR显示，内分泌胰腺特异性基因（包括Glut2和Pxd1）受到重大破坏，mRNA抑制分别达到54％（p  <0.001）和85.7％（p  = 0.01）。没有观察到与压力或凋亡基因相关的其他表达变化。扩展的临床随访涉及十个家庭成员，结果显示两个健康个体携带相同的突变，在临床筛查中没有发现糖尿病的征兆，但其中一个个体的IA-2抗体略有增加，表明外显率不完全。总之，我们描述EDEM2 作为一种可能的/潜在的新型糖尿病基因，其中体外抑制作用会降低葡萄糖刺激的胰岛素分泌（GSIS）途径中涉及的β细胞基因的表达，从而导致胰岛素分泌的整体抑制而不是细胞凋亡的抑制。