Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis.
The transition metal, copper (Cu), is an enzymatic cofactor required for a wide range of biochemical processes. Its essentiality is demonstrated by Menkes disease, an X-linked copper deficiency disorder characterized by defects in nervous-, cardiovascular- and skeletal systems, and is caused by mutations in the ATP7A copper transporter. Certain ATP7A mutations also cause X-linked Spinal Muscular Atrophy type 3 (SMAX3), which is characterized by neuromuscular defects absent an underlying systemic copper deficiency. While an understanding of these ATP7A-related disorders would clearly benefit from an animal model that permits tissue-specific deletion of the ATP7A gene, no such model currently exists. In this study, we generated a floxed mouse model allowing the conditional deletion of the Atp7a gene using Cre recombinase. Global deletion of Atp7a resulted in morphological and vascular defects in hemizygous male embryos and death in utero. Heterozygous deletion in females resulted in a 50% reduction in live births and a high postnatal lethality. These studies demonstrate the essential role of the Atp7a gene in mouse embryonic development and establish a powerful model for understanding the tissue-specific roles of ATP7A in copper metabolism and disease.
Department of Biochemistry, University of Missouri, Columbia, Missouri, United States of America.
Yanfang
Y
Wang
Sha
S
Zhu
Gary A
GA
Weisman
Jonathan D
JD
Gitlin
Michael J
MJ
Petris
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D047108:Embryonic Development / Q000235:genetics; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D023061:Gene Order; D018390:Gene Targeting; D005838:Genotype; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype
C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases