Menkes disease is a multi-systemic
copper metabolism disorder caused by mutations in the X-linked ATP7A gene and characterized by progressive neurodegeneration and severe connective tissue defects. The
ATP7A protein is a
copper (Cu)-transporting
ATPase expressed in all tissues and plays a critical role in the maintenance of
copper homeostasis in cells of the whole body. ATP7A participates in
copper absorption in the small intestine and in
copper transport to the central nervous system (CNS) across the blood-brain-barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Cu is essential for synaptogenesis and axonal development. In cells, ATP7A participates in the incorporation of
copper into Cu-dependent
enzymes during the course of its maturation in the secretory pathway. There is a high degree of homology (>80%) between the human ATP7A and murine Atp7a genes. Mice with mutations in the Atp7a gene, called mottled mutants, are well-established and excellent models of
Menkes disease. Mottled mutants closely recapitulate the Menkes phenotype and are invaluable for studying Cu-metabolism. They provide useful models for exploring and testing new forms of
therapy in
Menkes disease. Recently, non-mammalian models of
Menkes disease, Drosophila melanogaster and Danio rerio mutants were used in experiments which would be technically difficult to carry out in mammals.