ATP7A-related copper transport diseases-emerging concepts and future trends

Abstract

This Review summarizes recent advances in understanding copper-transporting ATPase 1 (ATP7A), and examines the neurological phenotypes associated with dysfunction of this protein. Involvement of ATP7A in axonal outgrowth, synapse integrity and neuronal activation underscores the fundamental importance of copper metabolism to neurological function. Defects in ATP7A cause Menkes disease, an infantile-onset, lethal condition. Neonatal diagnosis and early treatment with copper injections enhance survival in patients with this disease, and can normalize clinical outcomes if mutant ATP7A molecules retain small amounts of residual activity. Gene replacement rescues a mouse model of Menkes disease, suggesting a potential therapeutic approach for patients with complete loss-of-function ATP7A mutations. Remarkably, a newly discovered ATP7A disorder-isolated distal motor neuropathy-has none of the characteristic clinical or biochemical abnormalities of Menkes disease or its milder allelic variant occipital horn syndrome (OHS), instead resembling Charcot-Marie-Tooth disease type 2. These findings indicate that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology. Collectively, these insights refine our knowledge of the neurology of ATP7A-related copper transport diseases and pave the way for further progress in understanding ATP7A function.

Figure 1

Proposed mechanisms of copper transport to the CNS. a ∣ Copper delivery across the blood-brain barrier. ATP7A, ATP7B and CTR1 are expressed in brain capillaries. Copper delivery might occur via CTR1 and ATP7A, with return to the blood via ATP7B. Brain copper overload in Wilson disease (caused by mutations in ATP7B) is consistent with this hypothesis. b ∣ Proposed orientations of ATP7A and ATP7B for copper delivery across the blood–CSF barrier. c ∣ Activation of NMDARs at glutamatergic synapses triggers rapid, reversible ATP7A trafficking to axonal and dendritic processes, and copper efflux.^, Synaptic release of copper might competitively inhibit NMDAR-mediated calcium uptake, and modulate NMDAR activity in a neuroprotective fashion. Impaired ATP7A function might lead to prolonged, potentially deleterious NMDAR activation. d ∣ In norepinephrinergic neurons, ATP7A provides copper to DBH for conversion of dopamine to norepinephrine. A series of norepinephrine receptors and NETs handle the binding or reuptake of this neurotransmitter following synaptic release. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATP7A, copper-transporting ATPase 1; ATP7B, copper-transporting ATPase 2; CSF, cerebrospinal fluid; CTR1, copper transporter 1; DBH, dopamine-β-hydroxylase; MAO, monoamine oxidase; NET, norepinephrine transporter; NMDAR, N-methyl-d-aspartate receptor; PAM, peptidyl α-amidating monooxygenase; VMAT2, vesicular monoamine transporter 2.

Figure 2

Clinical phenotypes associated with mutations at the ATP7A locus. a ∣ Classic Menkes disease in a 20-month-old infant. Pectus excavatum deformity of the thorax and decorticate posturing can be observed. b ∣ Occipital horn syndrome in a 14-year-old boy. Narrow thorax, dislocated elbows, genu valgum and pes planus are all features of this disease. c ∣ Pes cavus foot deformity in a 43-year-old individual with the Pro1386Ser ATP7A missense mutation associated with Charcot–Marie–Tooth type 2-like peripheral neuropathy. Permission for part b obtained from Nature Publishing group © Kaler, S. G. et al. Nat. Genet. 8, 195–202 (1994). Part c reprinted from Am. J. Hum. Genet. 86, Kennerson, M. L. et al., Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy, 343–352 © 2010, with permission from The American Society of Human Genetics.

Figure 3

Topology of ATP7A missense mutations. ATP7A has eight transmembrane segments and six copper-binding domains. The protein also has phosphatase, phosphorylation, transduction and ATP-binding domains. The majority of ATP7A missense mutations affect the carboxy-terminal half of the protein. Early diagnosis and treatment is currently rare in Menkes disease; thus, little is known about the treatment responsivity of the missense mutations^,,,, associated with this phenotype. Of these mutations, only two (Gly666Arg [G666R] and Gly727Arg [G727R]) have been evaluated in terms of early intervention, and each proved responsive to treatment.^, Thus, newborn screening for Menkes disease that would detect affected infants in the first week of life is urgently needed. The locations of missense mutations that cause occipital horn syndrome and isolated distal motor neuropathy are also noted. Further details of the 47 ATP7A missense mutations are provided in Supplementary Table 3 online. Abbreviation: ATP7A, copper-transporting ATPase 1.

Figure 4

Yeast complementation assay predicts treatment response in Menkes disease. Plating pattern (clockwise from 12 o'clock) comprises yeast copper transport mutant ccc2Δ; ccc2Δ transformed with wild-type ATP7A; mock-transformed ccc2Δ; ccc2Δ transformed with mutant ATP7A harboring deletion of exons 20–23; ccc2Δ transformed with the Gly666Arg mutant ATP7A allele; and ccc2Δ transformed with the Asn1304Ser mutant ATP7A allele (associated with occipital horn syndrome). Only yeast expressing wild-type, Gly666Arg or Asn1304Ser ATP7A alleles showed growth on copper–iron-limited media, indicating that the proteins encoded by these variants retain some copper transport activity. The wild-type ATP7A allele-transformed yeast showed the most robust growth. The exon 20–23 deletion allele failed to complement ccc2Δ. Permission obtained from the Massachusetts Medical Society © Kaler, S. G. et al. N. Engl. J. Med. 358, 605–614 (2008).

Figure 5

Serial brain MRI scans from three patients with Menkes disease diagnosed and treated during the newborn period. a ∣ T2-weighted brain MRI scans from a patient with a Gly666Arg ATP7A mutation. b ∣ Axial FLAIR images from a patient with a splice junction mutation (IVS9 DS+6T>G) that had caused severe Menkes disease in an older sibling. c ∣ FLAIR images from a second patient with a Gly666Arg ATP7A mutation (this individual was unrelated to the other patient harboring this mutation). In all three individuals, mild signal changes on initial MRI examinations at 7–12 months disappeared in subsequent studies, indicating progressive white matter myelination. No evidence of cortical atrophy was seen in these patients. Abbreviations: ATP7A, copper-transporting ATPase 1; FLAIR, fluid-attenuated inversion recovery.

Figure 6

Proposed roles of ATP7A in motor neurons. Since various cuproenzymes (SOD1, CCO, ceruloplasmin and PAM), as well as copper transporters and chaperones (ATP7A, ATP7B, ATOX1, CCS and COX11), are expressed in mouse spinal cord, normal motor neuron function clearly seems to require copper. The discovery of ATP7A-related distal motor neuropathy, combined with case reports of peripheral neuropathy involving transient disturbances of copper metabolism, confirmed the importance of copper in these cells. Here, in addition to metallation of cuproenzymes, ATP7A is postulated to traffic down axons and mediate copper release from the axonal membrane of motor neurons and, possibly, at the neuromuscular junction. Golgi organelles and other translation machinery may reside within the axon itself, remote from the motor neuron cell body.^, Subtle but chronic metabolic insults produced by the Thr994Ile or Pro1386Ser mutations might engender the ‘dying back’ axonopathy that resembles Charcot–Marie–Tooth disease type 2. Abbreviations: ATOX1, copper transport protein ATOX1; ATP7A, copper-transporting ATPase 1; ATP7B, copper-transporting ATPase 2; CCO, cytochrome c oxidase; CCS, copper chaperone for SOD1; COX11, cytochrome c oxidase assembly protein COX11; COX17, cytochrome c oxidase copper chaperone; CTR1, copper transporter 1; DMT1, divalent metal transporter 1; PAM, peptidyl α-amidating monooxygenase; SCO1, protein SCO1 homolog; SOD1, copper–zinc superoxide dismutase.