Identification and functional characterization of a novel mutation in the NEUROD1 gene in a Chinese family with maturity-onset diabetes of the young
Abstract
Aims: Few 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.
Methods: WES 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.
Results: A 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).
Conclusions: A 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…
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