This model allows to explore changes in iron metabolism in suckling mutant mice suffering from systemic copper deficiency as well as in young and adult ones undergone copper therapy, which reduces lethal effect of the Atp7a gene mutation.
Copper disorders are divided into two classes: ATP7A- or ATP7B-related inherited copper transport disorders (Menkes disease, occipital horn syndrome, ATP7A-related distal motor neuropathy, and Wilson disease) and acquired diseases associated with copper deficiency or copper excess.
Adequate supplies of copper are particularly important in developing animals, and in humans this is illustrated by mutations of ATP7A that cause the copper deficiency condition Menkes disease, which is fatal in early childhood.
Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively.
L1373 at the end of transmembrane domain 8 is required for protein stability and Golgi retention in low copper, the trileucine motif (L1454-L1456) is required for retrograde trafficking, and the COOH terminus of ATP7B exhibits a higher sensitivity to copper than does ATP7A.
Here, we identify a mechanism by which organismal copper homeostasis is maintained by intestinal copper exporter trafficking that is coordinated with extraintestinal copper levels in Caenorhabditis elegans Specifically, we show that CUA-1, the C. elegans homolog of ATP7A/B, localizes to lysosome-like organelles (gut granules) in the intestine under copper overload conditions for copper detoxification, whereas copper deficiency results in a redistribution of CUA-1 to basolateral membranes for copper efflux to peripheral tissues.
Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency.
We hypothesized that gene expression changes in a MD patient with a lethal ATP7A mutation would indicate pathophysiological cascades relevant to the effects of copper deficiency in the developing brain.
Moreover, LC dysfunction caused by copper deficiency from ATP7A disruption can be rescued by restoring synaptic levels of NE, establishing a molecular CTR1-ATP7A-DBH-NE axis for copper-dependent LC function.
Menkes disease is an X-linked recessive copper deficiency disorder caused by mutations in the ATP7A ( MNK ) gene which encodes a copper transporting P-type ATPase (MNK).
Moreover, serum ceruloplasmin activity was decreased in the 110× and 38× (>90% reductions; P < 0.0001), and 18.5× (P < 0.001) and 9.5× (P < 0.05) (∼50% reductions) groups, typifying moderate to severe copper deficiency.
We determined the concentrations of copper, the activities of ceruloplasmin and peptidylglycine alpha-amidating monooxygenase (PAM), and the stimulation index of PAM by the in vitro addition of copper in plasma samples obtained from three male patients with occipital horns and a milder Menkes disease phenotype, having severe copper deficiency due to the defect in copper transport.
Presented are two cases of neurologic Wilson disease with progressive movement disorder and Kayser-Fleischer rings with low serum copper, lowceruloplasmin, and increased 24-hour urine copper against a background of normal transaminases.
Ceruloplasmin oxidase activity and serum free-copper concentration should be monitored in patients on long-term de-coppering therapy to prevent iatrogenic copper deficiency.