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The association between NUP133 (HGNC:18016) and Galloway-Mowat syndrome (MONDO_0009627) is supported by evidence from both individual case reports and multi‐patient studies. This neural and renal disorder is characterized by microcephaly, steroid‑resistant nephrotic syndrome, and focal segmental glomerulosclerosis (PMID:30427554).
In the primary study, a homozygous splicing variant, c.3335-11T>A, was identified in affected individuals, and its segregation within the family reinforced an autosomal recessive mode of inheritance (PMID:30427554). The mutation was shown to alter mRNA splicing through the abnormal retention of intronic sequence and was consistently observed in multiple affected patients.
Genetic evidence is bolstered by the demonstration that the altered NUP133 disrupts its interaction with NUP107, a critical nucleoporin. The immunoprecipitation assays and subsequent functional assessments using a zebrafish knockdown model recapitulated key features of Galloway-Mowat syndrome, including abnormal brain development and renal pathology (PMID:30427554).
Segregation analysis further supports this association; affected individuals within the reported family exhibit a clear segregation of the biallelic variant, with detailed clinical examinations confirming the phenotypic spectrum of brain anomalies and kidney dysfunction.
The integration of genetic and experimental evidence has led to a ClinGen gene–disease association rating of Strong. Robust segregation data, the recurrence of the c.3335-11T>A variant, and the concordance between functional assays and patient presentations provide high confidence in the pathogenicity of NUP133 deficiency in Galloway-Mowat syndrome.
This evidence not only reinforces the genetic diagnosis but also supports its use in clinical decision‑making. The detailed molecular characterization of the splicing defect guides both diagnostic confirmation and potential future therapeutic strategies.
Key Take‑home: Biallelic loss‑of‑function variants in NUP133 represent a strong and clinically actionable determinant of Galloway-Mowat syndrome, emphasizing the importance of incorporating molecular testing in patients with concurrent neural and renal abnormalities.
Gene–Disease AssociationStrongMultiple affected individuals in at least one family with clear segregation of the homozygous c.3335-11T>A variant and supporting functional data demonstrating disrupted NUP133/NUP107 interaction (PMID:30427554). Genetic EvidenceStrongThe recurrent homozygous splicing mutation c.3335-11T>A was identified in patients with Galloway-Mowat syndrome, with robust segregation evidence from the affected family and confirmation by molecular genetic analyses (PMID:30427554). Functional EvidenceModerateFunctional assays including immunoprecipitation and rescue experiments in a zebrafish model demonstrated that the mutant NUP133 impairs nucleoporin interactions and results in phenotypes that mimic GAMOS (PMID:30427554). |