ATP7A trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in ATP7A. (22nd April 2014) - Yi, Ling
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.