Decreased survival and hepato-renal pathology in mice with C-terminally truncated GP73 (GOLPH2).

Abstract

GP73 (Golph2) is a type II Golgi-localized integral membrane protein that is normally expressed in epithelial cells of many human tissues, and that is highly upregulated in liver disease. While its function is unknown, the GP73 C-terminus contains putative protein-interaction domains. We used a gene trap approach to generate mice with a severe truncation of the GP73 C-terminus (GP73(tr/tr)) in order to investigate the physiological role of this protein. GP73(tr/tr) mice were born at the expected rate and were fertile, but cumulative survival was significantly reduced compared to wild-type controls, particularly in females. GP73(tr/tr) mice developed varying degrees of renal disease, most notably focal segmental glomerulosclerosis and hyaline thrombi. In addition to renal abnormalities, GP73(tr/tr) mice developed marked microvesicular hepatic steatosis, hepatocyte nuclear membrane irregularities and intranuclear inclusions. GP73(tr/tr) expression in morphologically normal kidneys and livers was constitutively low, but was strikingly upregulated in the diseased kidney cortex, and was upregulated in livers in animals of advanced age. Despite the substantial morphological changes in the kidneys and liver, routine screening serum assays provided no evidence of renal or hepatic dysfunction. Consequently, the cause of the increased mortality of GP73(tr/tr) animals is unclear at present. Our study indicates that GP73 is essential for normal survival, and suggests multiple roles for GP73 in epithelial cell function in the kidney and liver.