Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence

Objective: The aim was to describe the clinical presentation and to characterize the genetic mutation present in a child with congenital malabsorptive diarrhea and neonatal diabetes. Research Design and Methods: Clinical data were obtained from chart review. Histopathological characterization of intestinal samples and neurogenin-3 (NEUROG3) sequencing were performed. Expression and function of the mutated NEUROG3 protein were assessed by Western blot analysis and luciferase reporter assay. Results: At birth, the proband was small for gestational age. She presented for evaluation with persistent diarrhea and a poor postnatal growth pattern. Although the pancreas was present, serum amylase and fecal elastase levels were decreased, and blood glucose levels were persistently elevated by 5 months of age. Immunostaining of a small intestine biopsy for chromogranin A demonstrated complete absence of neuroendocrine cells. Genetic analysis revealed a nonsense mutation (E123X) in the region encoding helix II of the NEUROG3 gene, leading to premature termination at amino acid 123. The mutated truncated NEUROG3 protein was identified by Western blot analysis. Reporter assays show decreased transactivation of the NEUROD1 promoter by mutant NEUROG3 protein as compared to wild type. Conclusions: This report describes a newly identified nonsense mutation in human NEUROG3 that in the homozygous state is associated with neonatal diabetes and malabsorptive diarrhea.