Submission Details

ATP7A encodes the copper-transporting ATPase alpha. In basal conditions, it is in the trans-Golgi Network (TGV) and transports copper to the cuproenzymes (copper metalloenzymes). However, in elevated copper concentrations, it localizes to the plasma membrane and facilitates the export of excess copper from the cells through exocytosis (Møller et al., PMID: 19501626). The gene was first mapped to chrXq13.3 in 1993 (Vulpe et al, PMID: 8490659; Mercer et al., PMID: 8490647; Chelly et al., PMID: 8490646) in patients with Menkes disease (MIM:309400) due to a loss of function mechanism in ATP7A. Partial loss of function is associated with occipital horn syndrome (MIM: 304150). Subnormal serum copper levels and early age of onset are characteristic for both phenotypes. In 2009, ATP7A was first reported in relation to X-linked recessive distal spinal muscular atrophy in two families (Kennerson et al., PMID: 20170900). These patients present during adulthood with progressive distal muscle weakness and atrophy without clinical or biochemical characteristics of systemic copper deficiency. Some patients show dysautonomic features (Gualandi et al., PMID: 31558336; Fradin et al., PMID: 33137485). Per criteria outlined by the ClinGen Lumping and Splitting Working group, we found a difference in molecular mechanism and phenotypic variability but no difference in inheritance pattern in the association of ATP7A with distal spinal muscular atrophy. Therefore, the following diseases entities have been split into the three before-mentioned entities: Menkes disease, Occipital Horn Syndrome and distal spinal muscular atrophy. Four different missense variants were reported of which three segregated in families (Kennerson et al., PMID: 20170900; Gualandi et al., PMID: 31558336) and one was sporadic (Fradin et al., PMID: 33137485). Two of these variants occur in the carboxyl half of the ATP7A protein, are highly conserved and absent in control populations (Kennerson et al., PMID: 20170900). Two other variants were predicted to be deleterious in in silico evaluations and were absent in control populations (Gualandi et al., PMID: 31558336; Fradin et al., PMID: 33137485). The gene-disease association is also supported by experimental evidence. Patient (Atp7A-T994I)-derived fibroblasts show reduced trans-Golgi-localization of ATP7A and more diffuse signals in cultured cells. Immunoprecipitation assays identified p97/VCP as an interaction protein (Yi et al., PMID: 22210628). Two mouse models were generated, a knock-in mouse (Atp7a-T994I) and a transgenic mouse (Atp7aMN/Y), with contradictory results. Herein the knock-in model showed no altered motor abilities or histological manifestations of acute or chronic neuropathy (Perez-Siles et al., PMID: 27293072), whereas the transgenic model exhibited progressive motor abnormalities and age-dependent loss of motor neuron cell bodies and denervation of the neuromuscular junction (Hodgkinson et al., PMID: 25639447). The mechanism of pathogenicity appears to be partial loss of function, altered protein-to-protein interaction (cfr. P97/VCP), and intracellular trafficking. In summary, ATP7A is moderately associated with x-linked distal spinal muscular atrophy. While more evidence is needed to establish this relationship definitely, no convincing contradictory evidence has emerged.