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This summary integrates multiple lines of evidence establishing a strong association between OSGEP mutations and Galloway-Mowat syndrome. The disease is characterized by a constellation of nephrological and neurological features including early-onset nephrotic syndrome, microcephaly, and developmental delay. The autosomal recessive inheritance pattern is consistently observed across diverse patient cohorts (PMID:28805828). Several independent case reports and multi‐patient studies have identified pathogenic OSGEP variants together with supportive clinical and genetic data, underscoring the robustness of this association (PMID:35812735). In total, more than 37 affected individuals from unrelated families have been documented, with clear segregation of pathogenic variants with the disease phenotype (PMID:28805828). This cumulative evidence supports diagnostic decision‑making and provides a foundation for further research and commercial test development.
Genetic evidence is underscored by the recurrent observation of specific OSGEP variant alleles. For example, the mutation c.974G>A (p.Arg325Gln) has been repeatedly identified in multiple studies and is observed in patients with both nephrological complications and urological manifestations such as recurrent urinary tract infections and hypercalciuria (PMID:30141175). Additional variants such as c.973C>G (p.Arg325Gly) and c.973C>T (p.Arg325Trp) further expand the mutational spectrum found in affected families. The aggregation of these findings across disparate case studies confirms the gene’s pivotal role in disease etiology. Detailed family segregation analyses have also provided insight into the deleterious effects of these alterations, reaffirming their clinical significance.
Segregation analysis across the various studies shows that affected individuals often harbor biallelic pathogenic variants that co‐segregate with the disease phenotype. Several studies have documented additional affected relatives in extended pedigrees, reinforcing the link between genotype and phenotype (PMID:30975089). This co‐segregation in independent familial settings further confirms the autosomal recessive mode of inheritance. The recurrent identification of the c.974G>A (p.Arg325Gln) variant in unrelated probands adds considerable weight to the genetic evidence. Hence, these data collectively support a robust genetic association between OSGEP alterations and Galloway-Mowat syndrome.
Functional studies have provided further important insights into the mechanism of pathogenicity. Experimental evaluations demonstrate that mutant OSGEP proteins exhibit abnormal subcellular localization and impaired function, contributing to the complex clinical phenotype observed. In cellular models, the mislocalization of OSGEP disrupts its normal role in the KEOPS complex, ultimately affecting protein synthesis and cellular homeostasis (PMID:34666032). Although these functional assays are largely consistent with the clinical manifestations, the experimental evidence is categorized as moderate given the variability in assay conditions and model systems. Nonetheless, these findings are instrumental in linking molecular dysfunction with the multisystem pathology seen in patients.
In summary, the combined genetic, segregation, and functional evidence firmly establishes a strong association between OSGEP mutations and Galloway-Mowat syndrome. The recurrent presence of the c.974G>A (p.Arg325Gln) variant among affected individuals and the consistent demonstration of disrupted OSGEP protein function provide a compelling basis for its clinical validity. This evidence not only informs current diagnostic workflows but also supports the development of future therapeutic strategies and commercial assays.
Key Take‑home Sentence: OSGEP mutations represent a critical molecular determinant of Galloway-Mowat syndrome, facilitating precise genetic diagnosis and guiding multidisciplinary patient management.
Gene–Disease AssociationStrongMultiple studies report over 37 affected individuals from unrelated families with consistent autosomal recessive inheritance and supportive functional evidence demonstrating OSGEP protein mislocalization and impaired activity (PMID:28805828, PMID:30141175). Genetic EvidenceStrongRecurrent pathogenic variants including c.974G>A (p.Arg325Gln) have been identified in affected probands and segregate in diverse families, confirming the genetic basis of the disease (PMID:35812735, PMID:30975089). Functional EvidenceModerateFunctional assays consistently demonstrate that OSGEP mutations lead to abnormal subcellular localization and loss-of-function effects that align with the Galloway-Mowat syndrome phenotype (PMID:34666032). |