Clinical and Functional Characteristics of a Novel Cys354Phe Variant Involved in Maturity-Onset Diabetes of the Young.

BACKGROUND

Mutations in human may lead to the development of maturity-onset diabetes of the young 7 (MODY7). This occurs due to impaired insulin synthesis in the pancreas. To date, the clinical and functional characteristics of the novel mutation c.1061G > T have not yet been reported.

METHODS

Whole-exon sequencing was used to screen the proband and family members with clinical suspicion of the variant. Luciferase reporter assays were used to investigate whether the variant binds to the insulin promoter. Real-time PCR, western blotting, and glucose-stimulated insulin secretion (GSIS) analysis were used to analyze the variant that regulates insulin expression and insulin secretion activity in beta cell lines. The Freestyle Libre H (Abbott Diabetes Care Ltd) was used to dynamically monitor the proband daily blood glucose levels.

RESULTS

Mutation screening for the whole exon genes identified a heterozygous (c.1061G > T) variant in the proband, her mother, and her maternal grandfather. Cell-based luciferase reporter assays using wild-type and mutant transgenes revealed that the (c.1061G > T) variant had impaired insulin promoter regulation activity. Moreover, this variant was found to impair insulin expression and insulin secretion in pancreatic beta cells. The proband had better blood glucose control without staple food intake ( < 0.05).

CONCLUSIONS

Herein, for the first time, we report a novel (c.1061G > T) monogenic mutation associated with MODY7. This variant has impaired insulin promoter regulation activity and impairs insulin expression and secretion in pancreatic beta cells. Therefore, administering oral antidiabetic drugs along with dietary intervention may benefit the proband.