Autosomal dominant diabetes associated with a novel ZYG11A mutation resulting in cell cycle arrest in beta-cells

Chutima CharoensukPrapaporn Jungtrakoon ThamtaranaChutima ChanprasertWatip TangjittipokinJun ShirakawaYu TogashiKazuki OrimePucharee SongprakhonChartchai ChaichanaZuroida AbubakarPaweena OuyingJatuporn SujjitjoonAlessandro DoriaNattachet PlengvidhyaPa thai YenchitsomanusYokohama City UniversityGunma UniversityFaculty of Medicine Siriraj Hospital, Mahidol UniversityHarvard Medical School2022-08-042022-08-042021-02-15Molecular and Cellular Endocrinology. Vol.522, (2021)18728057030372072-s2.0-85098469560https://repository.li.mahidol.ac.th/handle/20.500.14594/76279Diabetes is a genetically heterogeneous disease, for which we are aiming to identify causative genes. Here, we report a missense mutation (c.T1424C:p.L475P) in ZYG11A identified by exome sequencing as segregating with hyperglycemia in a Thai family with autosomal dominant diabetes. ZYG11A functions as a target recruitment subunit of an E3 ubiquitin ligase complex that plays an important role in the regulation of cell cycle. We demonstrate an increase in cells arrested at G2/mitotic phase among beta-cells deficient for ZYG11A or overexpressing L475P-ZYG11A, which is associated with a decreased growth rate. This is the first evidence linking a ZYG11A mutation to hyperglycemia, and suggesting ZYG11A as a cell cycle regulator required for beta-cell growth. Since most family members were either overweight or obese, but only mutation carriers developed hyperglycemia, our data also suggests the ZYG11A mutation as a genetic factor predisposing obese individuals to beta-cell failure in maintenance of glucose homeostasis.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyAutosomal dominant diabetes associated with a novel ZYG11A mutation resulting in cell cycle arrest in beta-cellsArticleSCOPUS10.1016/j.mce.2020.111126