Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side-product of glycolysis, methylglyoxal. It prevents dicarbonyl stress - the abnormal accumulation of reactive dicarbonyl metabolites increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with phenotype characterised as normal and healthy. Here we show that gene trapping mutation was successful but the presence of Glo1 gene duplication, likely in the embryonic stem cells before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in embryonic stem cells (ESCs), we found prolonged exposure of mouse ESCs in culture to high concentrations of methylglyoxal and/or hypoxia led to low level increase in Glo1 copy number. In clinical translation, we found increased prevalence of low level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low level copy number alternation in embryonic stem cells. Similar processes may drive rare GLO1 duplication in health and disease.
- copy number variation
- embryonic stem cell
- dicarbonyl stress
- ©2016 The Author(s)
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