title: In VivoModeling of the Pathogenic Effect of Copper Transporter Mutations That Cause Menkes and Wilson Diseases, Motor Neuropathy, and Susceptibility to Alzheimer's Disease.
abstract: Copper is an essential biometal, and several inherited diseases are directly associated with a disruption to normal copper homeostasis. The best characterized are the copper deficiency and toxicity disorders Menkes and Wilson diseases caused by mutations in the p-type Cu-ATPase genesATP7AandATP7B, respectively. Missense mutations in the C-terminal portion ofATP7Ahave also been shown to cause distal motor neuropathy, whereas polymorphisms inATP7Bare associated with increased risk of Alzheimer's disease. We have generated a single,in vivomodel for studying multiple pathogenic mutations in ATP7 proteins usingDrosophila melanogaster, which has a single orthologue of ATP7A and ATP7B. Four pathogenicATP7Amutations and twoATP7Bmutations were introduced into a genomicATP7rescue construct containing an in-frame C-terminal GFP tag. Analysis of the wild typeATP7-GFPtransgene confirmed that ATP7 is expressed at the basolateral membrane of larval midgut copper cells and that the transgene can rescue a normally early lethalATP7deletion allele to adulthood. Analysis of thegATP7-GFPtransgenes containing pathogenic mutations showed that the function of ATP7 was affected, to varying degrees, by all six of the mutations investigated in this study. Of particular interest, the ATP7BK832RAlzheimer's disease susceptibility allele was found, for the first time, to be a loss of function allele. Thisin vivosystem allows us to assess the severity of individualATP7A/Bmutations in an invariant genetic background and has the potential to be used to screen for therapeutic compounds able to restore function to faulty copper transport proteins.
authors.affiliation: From the School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Mercer
authors.affiliation: From the School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia richard.burke@monash.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Burke
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology*; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D005260:Female; D006527:Hepatolenticular Degeneration / Q000209:etiology*; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000209:etiology*; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*
chemical_list: C497836:ATP7 protein, Drosophila; D027682:Cation Transport Proteins; D000073840:Copper-Transporting ATPases
keywords: ATP7; ATP7A; ATP7B; Alzheimer disease; Drosophila; Menkes disease; Wilson disease; copper transport; intestinal metabolism; metal homeostasis