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.

Clusterin and COMMD1 Independently Regulate Degradation of the Mammalian Copper ATPases ATP7A and ATP7B

“…There is a high degree of clinical variability among patients (48) and mutation analysis of ATP7A and ATP7B has identified ϳ160 and 300 patient mutations for each gene, respectively (Wilson Disease Mutation Database, University of Alberta) (64). It has been suggested that the clinical outcome depends on the type of mutation (8,11,48). Individuals with identical mutations, including twins (65) and also between family members, can have vastly different clinical phenotypes (66,67), which suggests that other factors are involved in determining the clinical outcome of Menkes and Wilson diseases.…”

“…Defective copper transport across the basolateral membrane of these cells into the portal circulation leads to a systemic copper deficiency with devastating consequences (3,4,9,10). Biochemical abnormalities lead to neurological and developmental defects among many other symptoms (9,11). WD is an autosomal recessive copper toxicity disorder (9).…”

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…XLCL is caused by mutations in ATP7A, a copper transporter gene. 3,4 Diagnosis can be made based on clinical features, low serum levels of copper and ceruloplasmin and mutation analysis. 3,4 In autosomal dominant CL (MIM 123700), the family history, the appearance of skin signs and organ involvement is variable.…”

Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease

“…Along with the closely related ATPase ATP7B, ATP7A is a critical transporter of copper. Mutation of ATP7A is known to cause at least three distinct disorders (24), including Menkes disease (25)(26)(27), occipital horn syndrome (considered to be a milder form of Menkes disease) (28), and isolated distal motor neuropathy (29). Conversely, mutation of ATP7B causes Wilson disease (30,31), which is characterized by neuronal and hepatic pathologic processes associated with copper accumulation.…”