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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 G 2 /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.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This study investigated whether the body condition score (BCS) and/or culture influences the quality of life (QoL) of dogs, as evaluated by the owner, and whether the BCS is influenced by feeding and exercise and its owner's culture. To this end, a questionnaire was administered to 355 selected dog owners (Thai and Dutch). Their dogs had a BCS of 3 (normal weight), 4 (overweight) or 5 (obese) but no other physical problems. Instead of using Likert scales, continuous scales were used. Further, data for the questionnaire items were transformed using an integrated z-score methodology., Results: The magnitude of factor loadings was similar to that reported in a previous study, indicating that the questionnaire is not culture specific. QoL scores for general sickness were significantly higher (worse) in dogs with a higher BCS. Thus even though the dogs were apparently healthy, the BCS influenced the perceived QoL of the dog. Immobility was seen more often in dogs with a higher (poorer) BCS than in dogs with a lower (better) BCS; however, there was no clear relationship between immobility and total activity. The higher the BCS, the less owners felt in control of feeding and exercise. The BCS was higher in the dogs of owners who did not like to exercise. The Thai dogs showed more separation-related behaviour problems when their owner left home than did the Dutch dogs., Conclusions: The QoL of overweight and obese dogs is mainly influenced by the dog's physical status. The owners of dogs with a high BCS have less perceived control over feeding and exercise. Our findings indicate that owner attitudes and beliefs essentially cause obesity as a result of a lack of knowledge and perceived control.