novel mutation, Ser159Pro in the NeuroD1/BETA2 gene contributes to the development of diabetes in a Chinese potential MODY family

Objectives During examining the prevalence of mutations in NeuroD1/BETA2 gene in Chinese early-onset type 2 diabetic probands, a novel missense mutation, Ser159Pro in a potential MODY family was identified. To investigate the role of the mutation in early-onset diabetes, we studied its transcriptional activity on human insulin gene and clinical characteristics of the family with the mutation. Methods Bi-directional sequencing of NeuroD1/BETA2 was performed in 85 early-onset type 2 diabetic probands without mutations in HNF4α, glucokinase, HNF1α, IPF-1 and HNF1β genes, 95 late-onset type 2 diabetics with strong diabetic history and 87 non-diabetic control subjects. The function of the Ser159Pro to the transcription of a human insulin promotor-linked luciferase reporter gene in rat INS-1 cells was tested using Dual-Luciferase® Reporter Assay System. Clinical phenotypes of the family with the Ser159Pro mutation were examined and analyzed. Results A novel mutation, Ser159Pro were found in a 27-years-old proband with both parents had diabetes. The mutation was transmitted in the heterozygous state and co-segregated with diabetes in four out of five carriers from the paternal side. Expect for the proband, all of other members with this mutation in the family, however, were diagnosed with diabetes after 50-years-old. The functional study showed that the mutant protein exhibited a 25% reduction in transcriptional activity of insulin gene when compared with the wild type. Conclusions These results suggest that the novel Ser159Pro mutation in the NeuroD1/BETA2 gene contributes to the development of diabetes in a Chinese potential MODY family.