Galloway-mowat syndrome 3 (GAMOS3): a novel disease-causing variant in OSGEP gene and expansion of the clinical spectrum.

introductionGalloway-Mowat syndrome type 3 (GAMOS3) is a rare genetic disorder with renal and neurological complications caused by pathogenic variants in the OSGEP gene. Here, we report the molecular basis and clinical features in an Iranian family.

methodsOur proband, a 10-month-old female patient, presented with microcephaly, global developmental delay, lower limb spasticity, facial dysmorphisms, and renal tubulopathy. Brain magnetic resonance imaging (MRI), electroencephalography (EEG), and laboratory tests were performed to evaluate the clinical features. WES, Sanger sequencing, computational variant analysis, and gene expression analysis were conducted to identify, validate, and evaluate the genetic cause. Additionally, I-TASSER, HADDOCK, and GROMACS tools were utilized for protein modeling, computational docking, and molecular dynamics simulation (MDS), respectively.

resultsBlood and urine tests revealed proteinuria, hypercalciuria, and hypoalbuminemia. Brain MRI detected craniosynostosis, global parenchymal atrophy, and dysgenesis of the corpus callosum. Exome sequencing identified a previously unreported homozygous variant (NM_017807.4, c.689 G > T/p.C230F) in OSGEP, demonstrating co-segregation with the condition in the family. This missense variant did not significantly change the mRNA transcription. In-silico experiments predicted that this variant would likely alter the protein's structure and impair its normal functioning. Molecular docking results indicated that this variant significantly affects the protein interactions between OSGEP and LAGE3 proteins. Furthermore, MDS findings demonstrated that the p.C230F variant induced a conformational change in the mutant structure, potentially modifying its flexibility and stability.

conclusionIdentification of this variant contributes to expanding the OSGEP gene variant database, establishing a solid scientific foundation for precise clinical diagnosis and treatment.