Osgep-KO Mouse

Osgep, also known as O-sialoglycoprotein endopeptidase, is a crucial element of the highly conserved KEOPS complex. It is responsible for t6A37 modification of tRNANNU, which tunes glucose metabolism, and also plays a role in processes like protein translation, endoplasmic reticulum (ER) stress response, and cell proliferation [1,2,4]. The KEOPS complex, of which Osgep is a part, catalyzes an essential posttranscriptional modification of tRNA, highlighting its overall biological importance [4]. Genetic models such as knockout (KO) or conditional knockout (CKO) mouse models are valuable for studying Osgep.

Global Osgep deletion in mice causes glucose intolerance, while β-cell-specific deletion leads to hyperglycemia and glucose intolerance due to impaired insulin activity. Transcriptomics and proteomics in Osgep-deficient islets show activation of the unfolded protein response (UPR) and apoptosis signaling pathways, linked to misfolded proinsulin from reduced t6A37 modification. Overexpression of Osgep in the pancreas rescues insulin secretion and mitigates diabetes in high-fat diet mice [1]. In zebrafish and mice, CRISPR-Cas9 knockout of genes in the KEOPS complex, including Osgep, recapitulates the human phenotype of primary microcephaly and results in early lethality. Knockdown of Osgep in cell models inhibits cell proliferation, impairs protein translation, causes ER stress, activates DNA-damage-response signaling, and ultimately induces apoptosis [2].

In conclusion, Osgep is essential for maintaining proper islet β-cell function, glucose homeostasis, and normal development. Studies using KO/CKO mouse models have revealed its role in diabetes-related processes and in Galloway-Mowat syndrome, which is characterized by early-onset nephrotic syndrome and microcephaly with brain anomalies. Understanding Osgep's functions through these model-based research provides insights into potential therapeutic targets for diabetes and may help in early diagnosis and genetic counseling for Galloway-Mowat syndrome [1,2,3,5,6].