This report describes a model of uric acid nephrolithiasis using mutations of the Drosophila gene CG10939. CG10939 is orthologous to the human genes SLC9A3R1 and SLC9A3R2, also called NHERF1 and NHERF2, which encode adaptor/scaffolding proteins with diverse functions. The SLC9A3R1 gene has been implicated in the disease nephrolithiasis / osteoporosis, hypophosphatemic 2 (MIM:612287). Loss-of-function mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for CG10939. CG10939 is also homologous, but less closely related, to the human genes PDZD3 and PDZK1.
A UAS construct of the Hsap\SLC9A3R2 gene has been introduced into flies, but has not been characterized. The human SLC9A3R1 gene has not been introduced into flies.
Animals homozygous for amorphic mutations of CG10939 exhibit a very high number of small birefringent stones in the lumen of the Malpighian tubules (a structure analogous to the vertebrate kidney). A comparable phenotype is observed with RNAi-effected knockdown of CG10939 specifically in the stellate cells of the Malpighian tubules. This phenotype is abolished in rosy (ry) mutant flies (which model human xanthinuria, see FBhh0000095) and by the xanthine oxidase inhibitor allopurinol, suggesting that the calculi are of uric acid. Subsequently, the total concentration of uric acid in Malpighian tubules of CG10939 mutant flies was observed to be 8.5-fold higher compared with wild-type flies. Physical and genetic interactions of CG10939 have been described; see below and in the CG10939 gene report.
[updated Jul. 2020 by FlyBase; FBrf0222196]
SLC9A3R1 encodes a sodium/hydrogen exchanger regulatory cofactor; it is a scaffold protein that connects plasma membrane proteins with a number of different cytoplasmic proteins, including proteins that function as linkers between integral membrane and cytoskeletal proteins. The SLC9A3R1 protein interacts with a number of G-protein coupled receptors such as the beta2-adrenergic receptor and the parathyroid hormone 1 receptor. [Gene Cards, SLC9A3R1; 2020.07.27]
SLC9A3R2 encodes a member of the NHERF family of PDZ scaffolding proteins. These proteins mediate many cellular processes by binding to and regulating the membrane expression and protein-protein interactions of membrane receptors and transport proteins. [Gene Cards, SLC9A3R2; 2020.07.27]
SLC9A3R1 is a cytoplasmic adaptor protein that recruits various signaling proteins, cellular receptors, ion transporters, and other proteins to the plasma membrane of epithelia and other cell types (Wang et al., 2008; pubmed:18272783). [from MIM:604990; 2020.07.27
Many to one: multiple human genes to 1 Drosophila gene.
Many to one: multiple human genes to 1 Drosophila gene.
Moderate-scoring ortholog of human SLC9A3R1 and SLC9A3R2; lower-scoring ortholog of human PDZD3 and PDZK1(1 Drosophila to multiple human).
