This report describes Drosophila models of copper metabolism disorders, ATP7-related. The human genes ATP7A and ATPB encode transmembrane copper-transporting ATPases; both have been implicated in copper metabolism disorders. There is a single fly gene orthologous to the two human genes, Dmel\ATP7, for which classical hypomorphic alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Disruptions in copper homeostasis are implicated in a number of diseases associated with cognitive and motor deficits. Either excess amounts of or deficiencies of elemental copper result in cellular damage and disease. Menkes disease (MIM:309400, FBhh0000076) and occipital horn syndrome (MIM:304150, FBhh0000078), both associated with ATP7A, are copper deficiency disorders; Wilson disease (MIM:277900, FBhh0000079), associated with ATP7B, results from toxicity due to excess copper. Mutations in ATP7A are also implicated in neuronopathy, distal hereditary motor, X-linked (MIM:300489, FBhh0000077), however, serum copper concentrations are normal in individuals with this disease.
Multiple UAS constructs of the human Hsap\ATP7A gene have been introduced into flies, including wild-type and a variant implicated in disease. ATP7B has not been introduced into flies.
Variants analogous to those implicated in a number of the diseases associated with ATP7A or ATP7B have been characterized in flies. See the 'Disease-Implicated Variants' table below. In most cases, analogous mutations in the fly ATP7 gene have been characterized. The ATP7A:p.Met1311Val variant has been introduced in a transgenic copy of the human Hsap\ATP7A gene; this variant was isolated from an individual diagnosed with ALS.
A loss-of-function allele of the fly ATP7 gene is lethal during early larval stage when homozygous or hemizygous. Pan-neuronal overexpression of wild-type (tagged) Dmel\ATP7 results in reduced viability at all stages and visible adult phenotypes. Effected by gut-specific expression of RNAi directed against Dmel\ATP7, reduced levels in the digestive tract result in a reduced copper content in the head and body of surviving adults; a majority of these flies exhibit impaired neurological development during metamorphosis and die before eclosion.
[updated Feb. 2024 by FlyBase; FBrf0222196]
Many to one: 2 human to 1 Drosophila; the second human gene is ATP7A.
Many to one: 2 human to 1 Drosophila; the second human gene is ATP7B.
High-scoring ortholog of human genes ATP7A and ATP7B (1 Drosophila to 2 human). DmelATP7 shares 46-47% identity and 62% similarity with human genes.
