TY - JOUR T1 - Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males JF - bioRxiv DO - 10.1101/2020.06.29.177527 SP - 2020.06.29.177527 AU - Emily M. Walker AU - Jeeyeon Cha AU - Xin Tong AU - Min Guo AU - Jin-Hua Liu AU - Sophia Yu AU - Donato Iacovazzo AU - Franck Mauvais-Jarvis AU - Sarah E. Flanagan AU - Márta Korbonits AU - John Stafford AU - David Jacobson AU - Roland Stein Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/06/2020.06.29.177527.abstract N2 - A heterozygous missense mutation producing a variant of the islet β-cell-enriched MAFA transcription factor (Ser(S)64Phe(F) MAFA) was identified in humans who developed adult-onset, β-cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this variant impacts β cell function, we developed a mouse model expressing S64F MafA and found sex-dependent phenotypes, with heterozygous mutant males displaying impaired glucose tolerance while females were slightly hypoglycemic with improved blood glucose clearance. Only heterozygous males showed transiently higher MafA protein levels preceding the onset of glucose intolerance and sex-dependent, differential expression of genes involved in calcium signaling, DNA damage, aging, and senescence. Functional changes in islet calcium handling and signs of islet aging and senescence processes were uniquely observed in male animals. In addition, S64F MAFA expression in human, male EndoC-βH2 β cells accelerated cellular senescence and increased production of senescence-associated secretory proteins compared to cells expressing wild-type MAFA. Together, these results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in S64F MAFA carriers in a sex-dependent manner.Competing Interest StatementThe authors have declared no competing interest. ER -