Neonatal diabetes mellitus (NDM) is a hyperglycemic status usually diagnosed before first 6 months of life, which is caused by monogenic mutations. INS gene mutation is the second most common cause of permanent NDM, causing misfolding of proinsulin and accumulation in the endoplasmic reticulum, leading to apoptosis of the pancreatic beta cells. We report a case of NDM in a 2-month-old girl with a novel heterozygous mutation of the INS gene, and functional studies to confirm the pathogenesis of the mutation. A 2-month-old girl presented with mild fever, cough, and dyspnea for 2 days. The serum blood glucose was 702 mg/dl, pH 7.01, and serum and urine ketones were positive. She was diagnosed with NDM and diabetic ketoacidosis (DKA), and intravenous hydration and insulin infusion therapy were started. After resolution of DKA, she applied continuous glucose monitoring system and insulin pump. Next-generation sequencing revealed a novel heterozygous mutation in the INS gene. The newly discovered variant is c.64G>C (P.Ala22Pro). Further functional studies were performed to identify its clinical implications. Western blot analysis and RT-PCR showed decreased expression of protein and RNA in A22P mutant compared to wild-type, respectively. Insulin levels were lower in the mutant than in the wild type by ELISA. Confocal microscopy showed accumulation of human proinsulin proteins in the endoplasmic reticulum in A22P mutant. In conclusion, a novel mutation of the INS gene, c.64G>C (P.Ala22Pro), was discovered in a 2-month-old girl diagnosed with NDM, and decreased insulin secretion from pancreatic beta cells is confirmed based on various functional studies.
15 Sep 2022 - 17 Sep 2022