The NUP133 gene is located on chromosome 1 at q42.13 and encodes nucleoporin 133. Nucleoporin 133 is involved in poly(A)+ RNA transport and nephrogenesis (PMID:30179222). It also forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96. This complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus. It is expressed throughout the body, with disease-relevant expression noted in the kidney and brain.
Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity: Nephrotic syndrome, type 18 (OMIM:618177) and Galloway-Mowat syndrome 8 (OMIM: 618349). These two disease entities were lumped as part of the same spectrum of disease involving nephrotic syndrome with or without additional, extrarenal syndromic features.
NUP133 was first reported in relation to autosomal recessive nephrotic syndrome in 2018 (Braun et al., PMID: 30179222). Clinical presentation is generally characterized by nephrotic syndrome, focal segmental glomerulosclerosis, and proteinuria with or without additional neural phenotypes such as microcephaly and brain anomalies. The mechanism of pathogenicity is known to be loss of function.
Six variants (missense and intronic variants leading to frameshift) have been reported in four probands in three publications (PMIDs: 30179222, 30427554, 37041680) included in this curation. A total of 3.8/12 pts. for genetic evidence was reached, considering case-level data and segregation data.
This gene-disease relationship is also supported by functional studies, expression studies, in vitro assays in non-patient cells, and animal models. Morpholino knockdown of nup133 in Xenopus embryos and Nup133 in Zebrafish demonstrated abnormal pronephros morphology and phenocopied nephrotic syndrome respectively (PMIDs: 30179222, 30894603). Additionally, CRISPR/Cas9–mediated knockout of NUP133 increased the formation of filopodia in immortalized human podocytes, suggesting that loss of function of NUP133 alters the podocyte’s cytoskeleton (PMID: 30179222). Finally, NUP133 expression was demonstrated in the brain and kidney using a TaqMan assay (PMID: 30427554) and protein interaction with NUP107 was demonstrated by coimmunoprecipitation with the NUP160 subcomplex (PMID: 11564755). A total of 5/6 pts. for experimental evidence was reached.
In summary, there is moderate evidence supporting the relationship between NUP133 and autosomal recessive nephrotic syndrome.
This classification was approved by the ClinGen Glomerulopathy GCEP on the meeting date June 25, 2024 (SOP Version 10).
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