This report describes nephrotic syndrome, type 14 (NPHS14), a subtype of nephrotic syndrome; NPHS14 exhibits autosomal recessive inheritance. The human gene implicated in this disease is SGPL1 (sphingosine-1-phosphate lyase 1), an endoplasmic reticulum enzyme that is involved in sphingolipid catabolism. There is a single orthologous gene in Drosophila, Sply, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.
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].
The human SGPL1 gene has not been introduced into flies.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): S335I in the fly Sply gene [corresponds to S346I in the human SGPL1 gene]; R210Q in the fly Sply gene [corresponds to R222Q in the human SGPL1 gene]. Additional variant tested: E119G in the fly Sply gene [corresponds to E132G in the human SGPL1 gene]. Variants were tested for ability to rescue the semi-lethal phenotype of a Sply loss-of-function mutation.
Flies homozygous for a Dmel\Sply loss-of-function insertional mutation exhibit compromised muscle development, decreased fecundity, and semi-lethality. A small number of genetic and physical interactions have been described for Dmel\Sply; see below and in the Sply gene report.
[updated Sep. 2017 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]
[RENI SYNDROME; RENI](https://omim.org/entry/617575)
[SPHINGOSINE-1-PHOSPHATE LYASE 1; SGPL1](https://omim.org/entry/603729)
NPHS14 is an autosomal recessive syndromic form of steroid-resistant nephrotic syndrome with multisystemic manifestations. Most affected individuals present in infancy or or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS) and resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise (summary by Prasad et al., 2017, pubmed:28165343; Lovric et al., 2017, pubmed:28165339). [from MIM:617575; 2017.09.14]
Nephrotic syndrome 14 (NPHS14) is caused by homozygous or compound heterozygous mutation in the SGPL1 gene. [from MIM:617575; 2017.09.14]
Sphingolipids are components of all membranes but are particularly abundant in the myelin sheath (https://themedicalbiochemistrypage.org/sphingolipids.php).
SGPL1 encodes an endoplasmic reticulum (ER) enzyme that is involved in sphingolipid catabolism. Sphingosine-1-phosphate is a signaling sphingolipid that participates in various proliferative signal transduction pathways; its synthesis is catalyzed by sphingosine kinase and its degradation is catalyzed by sphingosine-1-phosphate lyase (SGPL1). [from MIM:603729; 2017.09.14]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human SGPL1 (1 Drosophila to 1 human). Dmel\Sply shares 50% identity and 69% similarity with the human gene.
