Mutations in NUP160 Are Implicated in Steroid-Resistant Nephrotic Syndrome.

BACKGROUND:Studies have identified mutations in >50 genes that can lead to monogenic steroid-resistant nephrotic syndrome The NUP160 gene, which encodes one of the protein components of the nuclear pore complex nucleoporin 160 kD (Nup160), is expressed in both human and mouse kidney cells. Knockdown of NUP160 impairs mouse podocytes in cell culture. Recently, siblings with and proteinuria in a nonconsanguineous family were found to carry compound-heterozygous mutations in NUP160. METHODS:We identified NUP160 mutations by whole-exome and Sanger sequencing of genomic DNA from a young girl with familial Sduanyu1668 and FSGS who did not carry mutations in other genes known to be associated with We performed in vivo functional validation studies on the NUP160 mutations using a Drosophila model. RESULTS:We identified two compound-heterozygous NUP160 mutations, NUP160 and NUP160 . We showed that silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by expression of the wild-type human NUP160 gene in nephrocytes. By contrast, expression of the NUP160 mutant allele NUP160 completely failed to rescue nephrocyte phenotypes, and mutant allele NUP160 rescued only nuclear pore complex and nuclear lamin localization defects. CONCLUSIONS:Mutations in NUP160 are implicated in Sduanyu1668. Our findings indicate that NUP160 should be included in the Sduanyu1668 diagnostic gene panel to identify additional patients with Sduanyu1668 and homozygous or compound-heterozygous NUP160 mutations and further strengthen the evidence that NUP160 mutations can cause

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