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Phenotypic diversity of menkes disease in mottled mice is associated with defects in localization and trafficking of the ATP7A protein
  1. Byung-Eun Kim
  1. University of Missouri-Columbia, United States
    1. Michael J Petris (petrism{at}
    1. University of Missouri-Columbia, United States


      Patients with Menkes disease suffer from inadequate supply of copper to various copper-dependent enzymes due to mutations in the copper-transporting P-type ATPase, ATP7A (or MNK). The ATP7A protein is located in the trans-Golgi network where it transports copper into secretory compartments to copper-dependent enzymes. Elevated copper concentrations result in the trafficking of ATP7A to the plasma membrane where it functions in copper export. An important model of Menkes disease is the collection of “Mottled” mice, which possess mutations in Atp7A. The Mottled mice display three distinct phenotypic severities, including embryonic lethality, perinatal lethality, a longer-lived viable phenotype. However, the effects of mutations from these phenotypic classes on the ATP7A protein are unknown. In this study, we demonstrate that these classes of mutation differentially affect the copper transport and trafficking functions of the ATP7A protein. The embryonic lethal mutation, Atp7amo11H (11H), caused mislocalization of the protein to the endoplasmic reticulum, impaired glycosylation, and abolished copper delivery to the secretory pathway. In contrast, the perinatal lethal and viable mutations, Atp7amoMac (Macular) and Atp7amoVbr (Viable brindle) both resulted in a reduction in copper deliver to the secretory pathway and constitutive trafficking of the ATP7A protein to the plasma membrane in the absence of additional copper. In the case of Viable brindle, this hyper-trafficking response was dependent on the catalytic phosphorylation site of ATP7A, whereas no such requirement was found for the Macular mutation. These findings provide evidence that the degree of Menkes disease severity in mice is associated with both copper transport and trafficking defects in the ATP7A protein.

      • ATP7A
      • Menkes disease
      • Mottled mice
      • copper
      • protein trafficking

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