Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome

Abstract

The nuclear pore complex (NPC) is a huge protein complex embedded in the nuclear envelope. It has central functions in nucleocytoplasmic transport, nuclear framework, and gene regulation. Nucleoporin 107 kDa (NUP107) is a component of the NPC central scaffold and is an essential protein in all eukaryotic cells. Here, we report on biallelic NUP107 mutations in nine affected individuals who are from five unrelated families and show early-onset steroid-resistant nephrotic syndrome (SRNS). These individuals have pathologically focal segmental glomerulosclerosis, a condition that leads to end-stage renal disease with high frequency. NUP107 is ubiquitously expressed, including in glomerular podocytes. Three of four NUP107 mutations detected in the affected individuals hamper NUP107 binding to NUP133 (nucleoporin 133 kDa) and NUP107 incorporation into NPCs in vitro. Zebrafish with nup107 knockdown generated by morpholino oligonucleotides displayed hypoplastic glomerulus structures and abnormal podocyte foot processes, thereby mimicking the pathological changes seen in the kidneys of the SRNS individuals with NUP107 mutations. Considering the unique properties of the podocyte (highly differentiated foot-process architecture and slit membrane and the inability to regenerate), we propose a "podocyte-injury model" as the pathomechanism for SRNS due to biallelic NUP107 mutations.

Homozygous mutation inNUP107leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome

“…Striking microcephaly was a consistent finding in all patients and was not reported in previously described patients with NUP107 mutations 9. The c.303G>A change in NUP107 was first reported among several genes involved in recessive intellectual disability, where the patient was reported to have kidney involvement.…”

“…Recently, compound heterozygous mutations in nucleoporin, 107-KD ( NUP107 ) were reported in nine patients with early onset nephrotic syndrome 9. While no neurological findings were noted, siblings carrying a homozygous NUP107 p.Met101Ile mutation showed focal segmental glomerulosclerosis (FSGS) and global developmental delay 10.…”

Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome

“…Gelsolin/villin proteins have been shown to serve important functions in regulating the actin organization. Here, we studied and characterized the role of AVIL for actin-bundling, -binding, and -severdown of AVIL, we performed siRNA-mediated knockdown of NUP107, a known monogenic cause of SRNS (25), in human podocytes and observed no effect on stress fibers compared with the scrambled siRNA-knockdown control (Supplemental Figure 8B). Upon stimulation with EGF, PLCE1 translocated to the lamellipodia (as described in ref.…”

Novel HPS6 mutations identified by whole-exome sequencing in two Japanese sisters with suspected ocular albinism

“…Trio samples (one affected individual and both parents) were analyzed by WES as previously described. 15 Given that there were two affected female children from the same healthy parents, autosomal recessive inheritance was presumed; therefore, homozygous and compound heterozygous variants were hypothesized as being causative mutations after filtering out variants with a minor allele frequency ⩾ 0.005 using ExAC (http://exac.broadinstitute.org/), Exome Variant Server (http://evs.gs. washington.edu/EVS/), Human Genetic Variation Database (http://www.genome.med.kyoto-u.ac.jp/SnpDB/), and in-house exome data (n = 575) and synonymous variants.…”