Mutations in <i>NUP160</i> Are Implicated in Steroid-Resistant Nephrotic Syndrome.

Abstract

Studies have identified mutations in >50 genes that can lead to monogenic steroid-resistant nephrotic syndrome (SRNS). The <i>NUP160</i> 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 <i>NUP160</i> impairs mouse podocytes in cell culture. Recently, siblings with SRNS and proteinuria in a nonconsanguineous family were found to carry compound-heterozygous mutations in <i>NUP160</i>. We identified <i>NUP160</i> mutations by whole-exome and Sanger sequencing of genomic DNA from a young girl with familial SRNS and FSGS who did not carry mutations in other genes known to be associated with SRNS. We performed <i>in vivo</i> functional validation studies on the <i>NUP160</i> mutations using a <i>Drosophila</i> model. We identified two compound-heterozygous <i>NUP160</i> mutations, <i>NUP160^R1173×</i> and <i>NUP160^E803K</i> . We showed that silencing of <i>Drosophila NUP160</i> 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 <i>NUP160</i> gene in nephrocytes. By contrast, expression of the <i>NUP160</i> mutant allele <i>NUP160^R1173×</i> completely failed to rescue nephrocyte phenotypes, and mutant allele <i>NUP160^E803K</i> rescued only nuclear pore complex and nuclear lamin localization defects. Mutations in <i>NUP160</i> are implicated in SRNS. Our findings indicate that <i>NUP160</i> should be included in the SRNS diagnostic gene panel to identify additional patients with SRNS and homozygous or compound-heterozygous <i>NUP160</i> mutations and further strengthen the evidence that <i>NUP160</i> mutations can cause SRNS.