Genetic background influences the heterogeneous phenotypes driven by the MAFAS64F MODY variant in male mice

Pancreatic {beta}-cells require the coordinated expression of transcription factors such as MAFA to dynamically secrete insulin to maintain euglycemia. A naturally occurring mutation in MAFA (MAFAS64F) produces a long-lived variant protein which predisposes carriers to dichotomous conditions of either maturity (adult)-onset diabetes of the young (MODY) or hypoglycemia in a sex-dependent manner. Here we show that genetic background modulates disease penetrance in MafAS64F/+ male mice. Specifically, MafAS64F/+ males backcrossed to a C57/Bl6J ("C57") background prevented dysglycemia, while C57 MafAS64F/+ males bred one generation to an SJL/J background ("mixed") manifested overt diabetes, impaired insulin secretion, and accelerated {beta}-cell senescence. MafA protein levels, phosphorylation status, and target gene expression in C57 MafAS64F/+ male islets were more comparable to wildtype males. RNA sequencing of C57 MafAS64F/+ male islets revealed fewer differentially expressed genes than mixed background male islets, including transcriptional signatures of {beta}-cell senescence. In addition, retinoic acid signaling, another signature of cellular aging, was uniquely downregulated in C57 MafAS64F/+ male islets. Indeed, core retinoic acid signaling receptor RAR and known target genes were downregulated in C57 MafAS64F/+ male islets. CUT&RUN mapping revealed that MafA directly impacted retinoic acid receptor alpha Rara expression. In sum, these data show that genetic factors can impact unique pathways to modulate disease penetrance in mice modeling MAFA-MODY. Article HighlightsO_LIGenetic background in mice or ancestry in humans can profoundly influence diabetes susceptibility. C_LIO_LIWe asked whether diabetes penetrance in our robust mouse model of MAFA-MODY on a mixed genetic background was impacted when backcrossed to C57/Bl6J ("C57"). C_LIO_LIHere we show that C57 MafAS64F/+ males have wildtype glucose-sensing properties, compared to overt diabetes which could be reproducibly re-created on a mixed background. Further analysis disclosed more muted gene expression changes in C57 MafAS64F/+ male islets including unique downregulation of senescence and retinoic acid signaling. C_LIO_LIThese results illustrate the influence of genetic landscape on {beta}-cell function in response to a pathogenic MODY variant. C_LI