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

Molecular and cellular endocrinology 2021 Feb 15

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Diabetes 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. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Chutima Charoensuk, Prapaporn Jungtrakoon Thamtarana, Chutima Chanprasert, Watip Tangjittipokin, Jun Shirakawa, Yu Togashi, Kazuki Orime, Pucharee Songprakhon, Chartchai Chaichana, Zuroida Abubakar, Paweena Ouying, Jatuporn Sujjitjoon, Alessandro Doria, Nattachet Plengvidhya, Pa-Thai Yenchitsomanus. Autosomal dominant diabetes associated with a novel ZYG11A mutation resulting in cell cycle arrest in beta-cells. Molecular and cellular endocrinology. 2021 Feb 15;522:111126