1767-P: A Modifying Effect of Genetic Background on S64F MAFA-Induced Dysglycemia

Introduction & Objective: The MAFA transcription factor is an essential regulator of mature pancreatic islet β cell function. A rare missense variant of human MAFA, Ser64Phe (S64F), was identified as a MODY gene in patients with familial insulinomatosis or diabetes mellitus (1). S64F MAFA carriers either became hypoglycemic due to multifocal pancreatic insulinomas (insulinomatosis) or develop diabetes, with men more likely to become diabetic and women develop insulinomatosis. A mouse model harboring this mutation recapitulated these sex-dependent glycemic phenotypes (2). Here we sought to investigate the impact of mouse genetic background on S64F MAFA-induced dysglycemia.

Methods: S64F MAFA mutant mice were bred either on a mixed C57/Bl6J (C57) and SJL background, or C57 alone. Glucose tolerance testing assessed serum glucose at t=0 (fasting), 15, 30, 60, and 90 minutes post intraperitoneal injection (0.2mg/kg dextrose). Statistical analysis was performed by Two-way ANOVA. Glucose-stimulated insulin secretion was also assessed at 0, 15 and 30 minute time points. Cut&Run determined DNA-protein interactions to help identify binding targets of MAFA in MIN6 β cells.

Results: Mixed background S64F MAFA male mice were diabetic while females showed improved tolerance compared to WT siblings. In the C57 background, males were euglycemic while females showed improved glycemia. Insulin secretion was impaired only in mixed background mutant males. Cut&Run analysis performed for endogenous MAFA in MIN6 cells identified enrichment at known MAFA targets such as Ins1, Ins2, and Slc2a2, among others, thus verifying our test system.

Conclusion: Genetic background influenced S64F MAFA-dependent glycemia in a sex-dependent manner. Ongoing studies investigate differential targets of this mutant MAFA compared to those of the wild-type protein by Cut&Run analysis within each sex and validate differential targets by RNAScope.