| First Author | Walker EM | Year | 2021 |
| Journal | Cell Rep | Volume | 37 |
| Issue | 2 | Pages | 109813 |
| PubMed ID | 34644565 | Mgi Jnum | J:328241 |
| Mgi Id | MGI:6881799 | Doi | 10.1016/j.celrep.2021.109813 |
| Citation | Walker EM, et al. (2021) Sex-biased islet beta cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males. Cell Rep 37(2):109813 |
| abstractText | A heterozygous missense mutation of the islet beta cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset beta cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women. This mutation engenders increased stability to the unstable MAFA protein. Here, we develop a S64F MafA mouse model to determine how beta cell function is affected and find sex-dependent phenotypes. Heterozygous mutant males (MafA(S64F/+)) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance. Only MafA(S64F/+) males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca(2+) signaling, DNA damage, aging, and senescence. MAFA(S64F) production in male human beta cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFA(WT). These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFA(S64F) carriers in a sex-biased manner. |
