Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males

• Published in: Cell reports (Cambridge) 2021-10, Vol.37 (2), p.109813-109813, Article 109813
• Main Authors: Walker, Emily M., Cha, Jeeyeon, Tong, Xin, Guo, Min, Liu, Jin-Hua, Yu, Sophia, Iacovazzo, Donato, Mauvais-Jarvis, Franck, Flanagan, Sarah E., Korbonits, Márta, Stafford, John, Jacobson, David A., Stein, Roland
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; beta cell; Blood Glucose - metabolism; Calcium Signaling; Cell Line; Cellular Senescence; diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Disease Models, Animal; DNA Damage; Female; Genetic Predisposition to Disease; Humans; Insulin - blood; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; islet biology; Maf Transcription Factors, Large - genetics; Maf Transcription Factors, Large - metabolism; MAFA; Male; Mice; Mice, Inbred C57BL; Mutation, Missense; Phenotype; Sex Characteristics; Sex Factors; sexual dimorphism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109813

A heterozygous missense mutation of the islet β cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset β 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 β cell function is affected and find sex-dependent phenotypes. Heterozygous mutant males (MafAS64F/+) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance. Only MafAS64F/+ males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca2+ signaling, DNA damage, aging, and senescence. MAFAS64F production in male human β cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFAWT. These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFAS64F carriers in a sex-biased manner. [Display omitted] •MafAS64F/+ mice show sex-dependent β cell dysfunction (diabetes or hypoglycemia)•MafAS64F/+ male and female mice show aberrant islet Ca2+ signaling•Only MafAS64F/+ males show markers of islet aging and senescence•MAFAS64F expression in male human EndoC-βH2 cells accelerates cellular senescence Walker et al. show that mice harboring the missense mutation of the pancreatic islet-enriched transcription factor MAFA (S64F MAFA) demonstrate sex-dependent β cell dysfunction, similar to findings in human carriers. Only male S64F MAFA β cells show accelerated senescence and β cell dysfunction toward hyperglycemia.