Open Close
General Information
Name
nephrotic syndrome, type 1
FlyBase ID
FBhh0000318
Disease Ontology Term
Parent Disease
Overview

This report describes nephrotic syndrome 1 (NPHS1), a subtype of nephrotic syndrome; NPHS1 exhibits autosomal recessive inheritance. The human gene implicated in this disease is NPHS1, nephrin, a kidney glomerular filtration barrier protein. There are two fly orthologs, sns and hbs, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles of both genes have been generated. The fly model of NPHS1 utilizes sns, since hbs is expressed in only a subset of nephrocytes.

A UAS construct of the wild-type Hsap\NPHS1 gene has been introduced into flies. Functional complementation could not be assessed, since even moderate overexpression of Hsap\NPHS1 produces abnormal phenotypes (FBrf0207370).

Animals homozygous for most loss-of-function mutations of sns die during the embryonic stage; embryonic garland cells lack nephrocyte diaphragms and lacunae. In targeted loss of function effected by RNAi, larval garland cells are also observed to be abnormal, with reduced numbers of nephrocyte diaphragms and lacunae.

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; the nephrocytes may also function in protein reabsorption [reviewed in FBrf0220711 and FBrf0235870; see also the human disease model report 'kidney disease (fly models overview)' FBhh0000738]. It is postulated that, analogous with NPHS1 and KIRREL in the slit diaphragm in mammals, Dmel\sns and Dmel\kirre interact through their extracellular domains to form the fly nephrocyte diaphragm (see FBhh0000549). The two fly genes have been shown to interact genetically and physically.

[updated Jun. 2017 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: nephrotic syndrome
Symptoms and phenotype

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 OMIM:256300, 2016.06.13]

Specific Disease Summary: nephrotic syndrome, type 1
OMIM report

[NEPHROTIC SYNDROME, TYPE 1; NPHS1](https://omim.org/entry/256300)

Human gene(s) implicated

[NEPHRIN; NPHS1](https://omim.org/entry/602716)

Symptoms and phenotype

Nephrotic syndrome type 1 (NPHS1) is characterized by prenatal onset of massive proteinuria followed by severe steroid-resistant nephrotic syndrome apparent at birth with rapid progression to end-stage renal failure (Kestila et al., 1998, pubmed:9660941). [From OMIM:256300, 2016.06.13]

Genetics

Nephrotic syndrome type 1 (NPHS1), also known as Finnish congenital nephrosis, is caused by homozygous or compound heterozygous mutation in NPHS1, the gene encoding nephrin. [From OMIM:256300, 2016.06.13]

Cellular phenotype and pathology

Electron microscopic studies of the kidney show effacement of the podocytes, a narrow slit, and absence of the slit diaphragm (Tryggvason et al., 2006, pubmed:16571882). Patients with congenital nephrotic syndrome exhibit an accumulation of type IV collagen in the renal cortex in renal biopsies. The accumulation of the collagen was out of proportion to another basement membrane protein, laminin. They interpreted this to mean that metabolism of type IV collagen is disturbed in this disorder (Risteli et al., 1982, pubmed:6122009). [From OMIM:256300, 2016.06.15]

Molecular information

NPHS1 encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes. [provided by RefSeq, Oct 2009]

The NPHS1 gene encodes nephrin, a kidney glomerular filtration barrier protein that is an essential component of the interpodocyte-spanning slit diaphragm (Wartiovaara et al., 2004, pubmed:15545998). [From OMIM:602716, 2016.06.15]

External links
Disease synonyms
CNF
congenital nephrotic syndrome
congenital nephrotic syndrome, Finnish type
Finnish congenital nephrosis
nephrotic syndrome type 1; NPHS1
NPHS1
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to many: 1 human to 2 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    sticks and stones (sns) encodes a single-pass transmembrane protein of the immunoglobulin superfamily, which mediates cell-cell recognition and adhesion. The product of sns marks the fusion competent population of myoblasts. It also contributes to formation and function of the nephrocyte diaphragm and cell sorting within the developing ommatidia. [Date last reviewed: 2019-03-14]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human NPHS1 (2 Drosophila to 1 human). Dmel\sns shares 29% identity and 45% similarity with human NPHS1.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (8 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot, bimolecular fluorescence complementation, fluorescence microscopy
      anti tag coimmunoprecipitation, western blot
      bead aggregation assay, fluorescence microscopy, inferred by author, anti tag coimmunoprecipitation, western blot, enzyme linked immunosorbent assay, anti tag western blot
      enzyme linked immunosorbent assay, bead aggregation assay, fluorescence microscopy, inferred by author
      enzyme linked immunosorbent assay, surface plasmon resonance
      Alleles Reported to Model Human Disease (Disease Ontology) (5 alleles)
      Models Based on Experimental Evidence ( 5 )
      Modifiers Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Interaction
      References
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      amorphic allele - genetic evidence
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      ethyl methanesulfonate
      References (12)