This report describes genetic models of calcium oxalate kidney stone disease in Drosophila. Mutations in human genes ATP6V1B1 and ATP6V0A4 have been identified in calcium oxalate kidney stone patients. ATP6V1B1 and ATP6V0A4 encode components of vacuolar ATPase (V-ATPase), a multi-subunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. Models of kidney stone disease in flies make use of the orthologous Drosophila genes, Vha55 and Vha100-2.
Both ATP6V1B1 and ATP6V0A4 are implicated in forms of distal renal tubular acidosis (MIM:267300, MIM:602722). A UAS construct of the human Hsap\ATP6V0A4 gene has been introduced into flies but has not been characterized. Human ATP6V1B1 has not been introduced into flies.
In insects, many of the functions of the vertebrate kidneys are carried out by structures known as Malpighian tubules (see FBhh0000738). Normally, Vha55 and Vha100-2 are highly expressed in the Malpighian tubules of larvae and adults. RNAi-mediated knockdown of either gene specifically in the Malpighian tubules results in conspicuously increased calcium oxalate crystal formation in Malpighian tubules, relative to controls. This system has been used to assess the efficacy of Garcinia cambogia extract in treatment of nephrolithiasis.
[updated Nov. 2020 by FlyBase; FBrf0222196]
Kidney stones (renal lithiasis, nephrolithiasis) are hard deposits made of minerals and salts that form inside the kidneys. (https://www.mayoclinic.org/diseases-conditions/kidney-stones/symptoms-causes/syc-20355755)
Mutations in ATP6V1B1 and ATP6V0A4 have been identified in calcium oxalate kidney stone patients (FBrf0246025 and references cited therein).
ATP6V1B1 and ATP6V0A4 encode components of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase-dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is present in endomembrane organelles such as vacuoles, lysosomes and endosomes. [Gene Cards, ATP6V1B1, ATP6V0A4; 2020.11.03]
Many to many: multiple related genes in both species.
Many to one: 2 human genes to 1 Drosophila gene; the human genes are ATP6V1B1 and ATP6V1B2.
High-scoring ortholog of human ATP6V1B2, moderate-scoring ortholog of ATP6V1B1. Dmel\Vha55 shares 89-91% identity and 93-94% similarity with the human genes.
Moderate-scoring ortholog of human ATP6V0A4, ATP6V0A2, and ATP6V0A1 (multiple related genes in both species). Dmel\Vha100-2 shares 51% identity and 68% similarity with ATP6V0A4.
