Identification and functional characterization of a novel mutation in the NEUROD1 gene in a Chinese family with maturity-onset diabetes of the young.

aimsFew families with maturity-onset diabetes of the young (MODY) caused by neurogenic differentiation factor 1 (NEUROD1) mutations have been identified. The aim of this study is to identify the affected gene in a Chinese family with MODY using whole exome sequencing (WES) and explore the potential pathogenicity of the identified mutation.

methodsWES was performed in patients with clinically suspected MODY, and candidate variants were verified with Sanger sequencing for family co-segregation. Structure-function alterations in the newly identified mutant protein were analyzed using three-dimensional modeling and dual luciferase reporter gene assays to assess pathogenicity.

resultsA novel heterozygous missense mutation, Y297D (c.889T > G, p.Tyr297Asp), in the NEUROD1 gene (NM_002500.5) was identified in a MODY proband and his affected relatives. Y297D mutation disrupted a C-H conjugated interaction and introduced a new hydrogen bond, altering the protein's local structure. These alterations reduced transcriptional activity in the transactivation domain of the Y297D mutant compared with that of the wild-type protein (P < .05).

conclusionsA novel NEUROD1 mutation has been identified in Chinese MODY, and the abnormal conformation of NEUROD1-Y297D reduced insulin transcription activity, impairing pancreatic β-cell function in patients with MODY6. Glucagon-like peptide-1 receptor agonist (GLP-1RAs) may be a precision hypoglycemic strategy to consider in diabetic patients with NEUROD1 mutations.