• nephrotic syndrome

This report describes nephrotic syndrome, KIRREL-related. There are 3 members of the nephrin-like protein family in human: KIRREL1 (also known as NEPH1), KIRREL2 (also known as NEPH2) and KIRREL3 (also known as NEPH3). All three genes are expressed in kidney podocytes; recently KIRREL1 has been implicated in a subtype of nephrotic syndrome (MIM:619201; FBhh0001330). There are two orthologous genes in Drosophila, rst and kirre, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles of both genes have been generated. This fly model of nephrotic syndrome utilizes kirre, since rst is expressed in only a subset of nephrocytes.

None of the human KIRREL genes has been introduced into flies, however the orthologous mouse genes Mmus\Kirrel, Mmus\Kirrel2, and Mmus\Kirrel3 have been. Based on work using the mouse genes, there is evidence that Dmel\kirre is functionally most similar to Mmus\Kirrel (KIRREL1) (FBrf0218912).

Animals homozygous for loss-of-function mutations of Dmel\kirre are viable and fertile. When homozygous, an amorphic mutation of kirre results in absence of filtration diaphragms and agglutination of nephrocytes (assayed in larvae). Genetic and physical interactions of Dmel\kirre have been described; see below and in the kirre gene report.

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 to NPHS1 and KIRREL1 in the slit diaphragm in mammals, Dmel\sns and Dmel\kirre interact through their extracellular domains to form the fly nephrocyte diaphragm (see FBhh0000318). The two fly genes have been shown to interact genetically and physically.

[updated Mar. 2021 by FlyBase; FBrf0222196]