Novel variants in OSGEP leading to Galloway-Mowat syndrome by altering its subcellular localization.

Galloway-Mowat syndrome (GAMOS) is an extremely rare clinically heterogeneous autosomal or X-linked inherited recessive disease characterized by early-onset steroid-resistant nephrotic syndrome (SRNS), microcephaly and neurological impairment. In this study, two siblings mainly presenting with decreased head circumference, hypotonia, gross motor delay, and dysmorphic features were initially detected without pathogenic variants by karyotyping, SNP-array and WES. After a 3 year's follow-up, the proband manifested additional proteinuria, hematuria and "deeper sulci" with a sign of brain atrophy. By reanalysis on the proband's previous WES data, two novel compound heterozygous variants of OSGEP (c.133dupA; c.608C > T) were identified. Furthermore, functional studies showed that the variants reduced the expression of OSGEP protein and activated the DNA damage response (DDR) signaling in the lymphoblastoid cell lines (LCLs) obtained from the patient. The analysis of protein localization with confocal microscopy revealed that the EGFP-tagged/HA-tagged mutant OSGEP proteins were abnormal aggregation or retained inside the cytosol, respectively. Our study not only expanded the pathogenic variant spectrum of OSGEP but also carried on regular follow-up for kidney involvement and established a strategy for evaluation on the function of mutant OSGFP by subcellular localization assay.