title: ATP7A trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in ATP7A.
abstract: Diverse mutations in the gene encoding the copper transporter ATP7A lead to X-linked recessive Menkes disease or occipital horn syndrome. Recently, two unique ATP7A missense mutations, T994I and P1386S, were shown to cause isolated adult-onset distal motor neuropathy. These mutations induce subtle defects in ATP7A intracellular trafficking resulting in preferential accumulation at the plasma membrane compared to wild-type ATP7A. Immunoprecipitation assays revealed abnormal interaction between ATP7A(T994I) and p97/VCP, a protein mutated in two autosomal dominant forms of motor neuron disease. Small-interfering RNA knockdown of valosin-containing protein corrected ATP7A(T994I) mislocalization. For ATP7A(P1386S) , flow cytometry documented that nonpermeabilized fibroblasts bound a C-terminal ATP7A antibody, suggesting unstable insertion of the eighth transmembrane segment due to a helix-breaker effect of the amino acid substitution. This could sabotage interaction of ATP7A(P1386S) with adaptor protein complexes. These molecular events appear to selectively disturb normal motor neuron function and lead to neurologic illness that takes years and sometimes decades to develop.
authors.affiliation: Section on Translational Neuroscience, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ling
authors.initials: L
authors.lastname: Yi
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaler
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D003483:Cutis Laxa / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D021381:Protein Transport / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000074405:Valosin Containing Protein
chemical_list: D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D034741:RNA, Small Interfering; D003300:Copper; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
keywords: ATP7A; adaptor protein complexes; distal motor neuropathy; p97/VCP
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