Menkes disease is a recessive X-linked disorder that causes lethal copper deficiency. It results from mutations in a copper exporter gene, ATP7A, expressed in the gut. As a consequence of these mutations, copper is trapped in the gut of Menkes patients and cannot be delivered to the brain, resulting in severe neurological abnormalities, seizures and early death. Patients are also characterized by coarse thin hair and growth defects. Current disease treatments supply copper by subcutaneous or intravenous injection, but are not very effective. If treatment is started prenatally or perinatally, some neurodegeneration is prevented and survival can be enhanced, but non-neurological abnormalities are still present. To develop better treatments, more needs to be known about the pathogenesis of the disorder, and the complex nature of the disease requires whole-organism approaches. Although mouse models have been developed, a simpler, faster and cheaper model system such as Drosophila would also be of use.

This paper describes a new Drosophila model of Menkes disease. The authors silence the Drosophila DmATP7 copper exporter gene in the digestive tract to mimic the human disease. Copper is trapped in the gut of the mutant, preventing copper delivery to other parts of the fly’s body, including the head. Mutant flies exhibit severe neurological abnormalities and die at an early age, similar to human patients. Expression of the copper homeostasis gene MTF-1, which is thought to play a role in Menkes disease, rescues the lethal phenotype, suggesting that MTF-1 induction may be used as a supplementary approach for the treatment of Menkes disease.

This fly model recapitulates major features of human Menkes disease. The powerful genetic tools that are available for manipulation of Drosophila make it a cost-effective and simple system for the identification and validation of other genes involved in the Menkes disease phenotype, and for screening of future therapeutics.

2010