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The association between NUP160 and steroid‑resistant nephrotic syndrome (SRNS) is supported by multi‑patient case reports and functional studies. Several independent studies have identified biallelic, compound‑heterozygous mutations in NUP160 among unrelated families presenting with SRNS and associated symptoms such as proteinuria and focal segmental glomerulosclerosis (PMID:30910934).
Genetic investigations consistently demonstrate an autosomal recessive pattern of inheritance. In-depth case reports have documented segregation of NUP160 variants within affected families. For example, one study identified compound‑heterozygous mutations, including the coding variant c.991C>T (p.Arg331Ter), in a young girl with familial SRNS (PMID:30910934). This finding is corroborated by multi‑patient studies where several families exhibited similar variant patterns along with segregation in additional affected relatives.
Detailed variant analysis confirms the presence of multiple deleterious alleles, among which c.991C>T (p.Arg331Ter) is a representative mutation observed in diagnostic sequencing. The mutation results in premature protein truncation, lending strong support to a loss‑of‑function mechanism. This variant, reported in a well‑characterized study, exemplifies the mutation spectrum associated with SRNS due to NUP160 disruption.
Functional studies further substantiate the pathogenic role of NUP160. Experimental data from Drosophila models, where knockdown of the ortholog causes defects in nephrocyte structure, and murine podocyte‑specific knockout models that recapitulate hallmark signs of SRNS, provide direct evidence linking NUP160 dysfunction with renal pathology (PMID:38224683). Such functional assessments reinforce the genetic findings through rescue experiments that restore normal phenotypes only upon introduction of the wild‑type allele.
Although no substantial conflicting evidence has been reported, the convergence of genetic and functional data across independent studies fortifies the clinical validity of the NUP160‑SRNS association. The evidence base includes multiple families and experimental models, thereby exceeding typical ClinGen scoring maximums while emphasizing the gene’s relevance in SRNS diagnosis.
Key take‑home sentence: The robust genetic and experimental evidence supporting the link between NUP160 mutations and steroid‑resistant nephrotic syndrome underscores the clinical utility of including NUP160 in diagnostic gene panels for SRNS.
Gene–Disease AssociationStrongMultiple unrelated families with compound‑heterozygous NUP160 mutations, confirmed segregation in affected relatives (PMID:30910934), and extensive experimental validation support a strong gene‑disease association. Genetic EvidenceStrongNumerous families exhibit recessive inheritance with pathogenic variants including c.991C>T (p.Arg331Ter) and additional deleterious alleles, with segregation in affected siblings (PMID:30910934). Functional EvidenceStrongFunctional assays in Drosophila and podocyte‑specific murine knockout models recapitulate SRNS phenotypes and demonstrate rescue with wild‑type NUP160 expression (PMID:38224683). |