This report describes focal segmental glomerulosclerosis 3 (FSGS3), which is a subtype of focal segmental glomerulosclerosis; this disease is also described as a form of nephrotic syndrome (FBhh0000317). The gene implicated in FSGS3 is CD2AP (CD2 associated protein), which encodes an adapter protein between membrane proteins and the actin cytoskeleton. Haploinsufficiency of the CD2AP locus results in dominant inheritance of FSGS3, but at least one disease-associated variant exhibits autosomal recessive inheritance. There is a single orthologous gene in Drosophila, cindr, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. Dmel\cindr is orthologous to two additional human genes, SH3KBP1 and SH3D21. CD2AP has also been implicated in susceptibility to Alzheimer disease(FBhh0000260).
Multiple UAS constructs of the human Hsap\CD2AP gene have been introduced into flies, including wild-type and a variant tentatively associated with development of nephrotic syndrome. Variant(s) implicated in human disease tested (as transgenic human gene, CD2AP): the Y10F and K301M variant forms of the human gene have been introduced into flies. Partial heterologous rescue (functional complementation) has been demonstrated using the wild-type human transgene, assaying nephrocyte phenotypes, eye patterning phenotypes, and adult lifespan; rescue is not observed using the Y10F or K301M variant forms.
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].
RNAi-effected reduction of cindr function in nephrocytes results in nephrocyte functional impairment and structural abnormalities; the animals also exhibit shortened adult life span. Extensive physical and genetic interactions of Dmel\cindr have been reported; see below and in the gene report for cindr.
[updated January 2020 by FlyBase; FBrf0222196]
Focal segmental glomerulosclerosis is one of many diseases and conditions can affect kidney function by attacking and damaging the glomeruli. "Glomerulosclerosis" refers to a hardening and scarring of the glomeruli. The scarring of FSGS takes place in small sections of each glomerulus, and only a limited number of glomeruli are damaged initially (https://www.kidney.org/atoz/content/focal).
A definitive diagnosis of FSGS is established only by histopathology findings (http://emedicine.medscape.com/article/245915-overview).
Focal segmental glomerulosclerosis (FSGS) is a pathologic finding in several renal disorders that manifest clinically as proteinuria and progressive decline in renal function. Some patients with FSGS develop nephrotic syndrome, which includes massive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. However, patients with FSGS may have proteinuria in the nephrotic range without other features of the nephrotic syndrome (summary by D'Agati et al., 2004, pubmed:14750104; Mathis et al., 1998, pubmed:9461087). [from MIM:603278; 2017.09.14]
Focal segmental glomerulosclerosis is a common cause of end-stage renal disease (Meyrier, 2005; pubmed:16932363). [from MIM:607832; 2017.09.14]
In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature. [from MIM:607832; 2017.09.14]
[FOCAL SEGMENTAL GLOMERULOSCLEROSIS 3, SUSCEPTIBILITY TO; FSGS3](https://omim.org/entry/607832)
[CD2-ASSOCIATED PROTEIN; CD2AP](https://omim.org/entry/604241)
See general description of focal segmental glomerulosclerosis.
Susceptibility to focal segmental glomerulosclerosis-3 (FSGS3), is conferred by haploinsufficiency for CD2-associated protein (CD2AP). [from MIM:607832; 2017.09.14]
At least one mutation of CD2AP implicated in FSGS3 (R612X, truncation of last 27aa) exhibits autosomal recessive inheritance. [from MIM:604241; 2017.09.14]
CD2AP is known to be a crucial protein for the slit-diaphragm assembly and function (Gigante et al., 2009; pubmed:19131354).
CD2AP encodes an adapter protein between membrane proteins and the actin cytoskeleton that directly interacts with filamentous actin and a variety of cell membrane proteins. One of its many functions appears to be anchoring the podocyte slit diaphragm to the actin cytoskeleton in renal glomeruli. [from Gene Cards, CD2AP; 2017.09.14]
Many to one: 3 human to 1 Drosophila; the additional human genes are SH3KBP1 and SH3D21.
Moderate-scoring ortholog of human CD2AP and SH3KBP1; low-scoring ortholog of SH3D21 (1 Drosophila to 3 human). Dmel\cindr shares 22-26% identity and 32-36% similarity with the human genes.
