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Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease

Skjørringe, Tina; Amstrup Pedersen, Per; Salling Thorborg, Sidsel; Nissen, Poul; Gourdon, Pontus LU and Birk Møller, Lisbeth (2017) In Scientific Reports 7.
Abstract

Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. Here we have analyzed the effect of 36 ATP7A missense mutations identified in phenotypically different MD patients. Nine mutations identified in patients with severe MD, virtually eliminated ATP7A synthesis, in most cases due to aberrant RNA splicing. A group of 21 predominantly severe mutations led to trapping of the protein in TGN and displayed essentially no activity in a yeast-based functional assay. These were predicted to inhibit... (More)

Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. Here we have analyzed the effect of 36 ATP7A missense mutations identified in phenotypically different MD patients. Nine mutations identified in patients with severe MD, virtually eliminated ATP7A synthesis, in most cases due to aberrant RNA splicing. A group of 21 predominantly severe mutations led to trapping of the protein in TGN and displayed essentially no activity in a yeast-based functional assay. These were predicted to inhibit the catalytic phosphorylation of the protein. Four mutants showed diffuse post-TGN localization, while two displayed copper dependent trafficking. These six variants were identified in patients with mild MD and typically displayed activity in the yeast assay. The four post-TGN located mutants were presumably affected in the catalytic dephosphorylation of the protein. Together these results indicate that the severity of MD correlate with cellular localization of ATP7A and support previous studies indicating that phosphorylation is crucial for the exit of ATP7A from TGN, while dephosphorylation is crucial for recycling back to TGN.

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author
organization
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Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
7
publisher
Nature Publishing Group
external identifiers
  • scopus:85018994225
ISSN
2045-2322
DOI
10.1038/s41598-017-00618-6
language
English
LU publication?
yes
id
83556c44-7713-43f7-aa74-90726dfbecf5
date added to LUP
2017-04-29 15:25:48
date last changed
2018-01-07 12:01:07
@article{83556c44-7713-43f7-aa74-90726dfbecf5,
  abstract     = {<p>Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper-transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations. Here we have analyzed the effect of 36 ATP7A missense mutations identified in phenotypically different MD patients. Nine mutations identified in patients with severe MD, virtually eliminated ATP7A synthesis, in most cases due to aberrant RNA splicing. A group of 21 predominantly severe mutations led to trapping of the protein in TGN and displayed essentially no activity in a yeast-based functional assay. These were predicted to inhibit the catalytic phosphorylation of the protein. Four mutants showed diffuse post-TGN localization, while two displayed copper dependent trafficking. These six variants were identified in patients with mild MD and typically displayed activity in the yeast assay. The four post-TGN located mutants were presumably affected in the catalytic dephosphorylation of the protein. Together these results indicate that the severity of MD correlate with cellular localization of ATP7A and support previous studies indicating that phosphorylation is crucial for the exit of ATP7A from TGN, while dephosphorylation is crucial for recycling back to TGN.</p>},
  articleno    = {757},
  author       = {Skjørringe, Tina and Amstrup Pedersen, Per and Salling Thorborg, Sidsel and Nissen, Poul and Gourdon, Pontus and Birk Møller, Lisbeth},
  issn         = {2045-2322},
  language     = {eng},
  month        = {04},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease},
  url          = {http://dx.doi.org/10.1038/s41598-017-00618-6},
  volume       = {7},
  year         = {2017},
}