ABSTRACT
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.
Subject(s)
Cell Cycle Checkpoints/genetics , Cell Cycle Proteins/genetics , Diabetes Mellitus/genetics , Genes, Dominant , Insulin-Secreting Cells/pathology , Mutation/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Cell Cycle Proteins/chemistry , Cell Proliferation/genetics , Chromosome Segregation/genetics , Exome/genetics , Female , Humans , Male , Middle Aged , Models, Biological , Models, Molecular , PedigreeABSTRACT
Maturity-onset diabetes of the young type 3 (MODY3) is caused by mutations in a gene encoding transcription factor hepatocyte nuclear factor 1-alpha (HNF1A). Although the roles of HNF1A in regulation of hepatic and pancreatic genes to maintain glucose homeostasis were investigated, the functions of HNF1A are not completely elucidated. To better understand the functions of HNF1A, we characterized mutations of HNF1A in Thai MODY3 patients and studied the functions of wild-type HNF1A and variant proteins. We demonstrate for the first time that HNF1A upregulates transactivation of an anti-apoptotic gene BCL2 Like 1 (BCL2L1) and that all the identified HNF1A variants including p.D80V, p.R203C, p.P475L, and p.G554fsX556, reduce this ability. The four HNF1A variants impair HNF1A function in promoting INS-1 cell transition from G1 to S phase of cell cycle, which thereby retard cell growth. This finding indicates the role of HNF1A in beta-cell viability by upregulation of anti-apoptotic gene expression and also reaffirms its role in beta-cell growth through cell cycle control.
