This report describes nephrotic syndrome type 19, which shows autosomal recessive inheritance. (Many genes have been associated with a subtype of nephrotic syndrome, see the phenotypic series below.) The human gene implicated in this disease is NUP160. There is a single high-ranking ortholog of NUP160 in Drosophila, Nup160. Several alleles have been generated for Nup160, including RNAi targeting constructs, overexpression constructs, hypomorphic alleles, and insertions.
The human gene NUP160 has been introduced into flies (Hsap\NUP160). Heterologous rescue (functional complementation) of Dmel\Nup160 with human Hsap\NUP160 has been demonstrated. Variants implicated in human disease have been characterized. Variant(s) implicated in human disease tested (as transgenic human gene, NUP160): the E803K and R1173X variant forms of the human gene have been introduced into flies.
In the fly, nephrocytes act in a manner analogous to human podocytes: the fly nephrocyte diaphragm functions like the mammalian slit diaphragm to regulate filtration, and the nephrocytes may also function in protein reabsorption. These functions have been reviewed in FBrf0220711 and FBrf0235870; see also the human disease model report 'kidney disease (fly models overview)' FBhh0000738.
Nup160 knockdown in fly nephrocytes causes larvae to have fewer nephrocytes than normal. Larval nephrocytes perform worse at multiple measures of nephrocyte function, including their capability to sequester a toxic dietary additive, silver nitrate. Mutant nephrocyte nuclei have an irregular structure, similar to nuclei lacking Lam. Adult mutants have no nephrocytes and a reduced lifespan. Overexpressing human NUP160 in Nup160 knockdown flies rescues these phenotypes, and has no deleterious effect on its own. However, overexpressing human variant Hsap\NUP160E803K.UAS in Nup160 knockdown flies only partially rescues, while the variant Hsap\NUP160R1173X.UAS acts as a null mutation and cannot rescue any function.
[updated June 2019 by FlyBase; FBrf0222196]
The nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al., 1996, pubmed:8606597). [From MIM:256300, 2016.06.13]
[NEPHROTIC SYNDROME, TYPE 19; NPHS19](https://omim.org/entry/618178)
[NUCLEOPORIN, 160-KD; NUP160](https://omim.org/entry/607614)
Nephrotic syndrome is a renal disease caused by disruption of the glomerular filtration barrier, resulting in massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. (Zhao et al. 2019, FBrf0242226.)
Twenty-five individuals of 13 families with recessive mutations of NUP107, NUP85, NUP133, or NUP160 had SRNS or proteinuria that manifested in childhood or adolescence. In 13 of these 25 patients, the disease progressed to end-stage renal disease (ESRD) before age 25 years. (Braun et al. 2018, pubmed:30179222.)
Nephrotic syndrome is characterized clinically by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. Approximately 20% of affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure (summary by Fuchshuber et al. 1996, pubmed:8606597). [from MIM:256300, 2019.07.02]
Studies have identified mutations in more than 50 genes that can lead to monogenic steroid-resistant nephrotic syndrome (SRNS). These include genes encoding components of the slit diaphragm, such as NPHS1, NPHS2, and CD2AP; genes encoding actin cytoskeleton proteins, such as ACTN4, INF2, and MYO1E; genes encoding actin-regulating small GTPases of the Rho/Rac/Cdc42 family, including ARHGDIA, ARHGAP24, and KANK; and genes encoding nucleoporins (Nups), including NUP93, NUP107, and NUP205. (Zhao et al. 2019, FBrf0242226.)
Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Mutations have been found in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, it was shown that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. (from Braun et al. 2018, pubmed:30179222)
In 2 Chinese siblings (family 17F00494) with NPHS19, Braun et al. 2018 (pubmed:30179222) identified compound heterozygous mutations in the NUP160 gene. The patients were part of a large study in which various nucleopore (NUP) genes were found to be mutated in NPHS, suggesting a common pathogenic pathway. [from OMIM , 2019.07.02]
NUP160 encodes a direct interaction partner of NUP85 within the Y complex, the major subunit of the outer rings of the nuclear pore complex. (Braun et al. 2018, pubmed:30179222.)
One to one: 1 human gene to 1 Drosophila gene.
High-ranking ortholog of human NUP160.
