Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease
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 c...
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doaj-31afdcd2171345e18a1b524b05516b282020-12-08T00:07:13ZengNature Publishing GroupScientific Reports2045-23222017-04-017111810.1038/s41598-017-00618-6Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes diseaseTina Skjørringe0Per Amstrup Pedersen1Sidsel Salling Thorborg2Poul Nissen3Pontus Gourdon4Lisbeth Birk Møller5Applied Human Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen UniversityDepartment of Biology, August Krogh Building, University of CopenhagenApplied Human Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen UniversityCentre for Membrane Pumps in Cells and Disease-PUMKIN, Aarhus University, Department of Molecular BiologyDepartment of Biomedical Sciences, University of CopenhagenApplied Human Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen UniversityAbstract 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.https://doi.org/10.1038/s41598-017-00618-6 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tina Skjørringe Per Amstrup Pedersen Sidsel Salling Thorborg Poul Nissen Pontus Gourdon Lisbeth Birk Møller |
spellingShingle |
Tina Skjørringe Per Amstrup Pedersen Sidsel Salling Thorborg Poul Nissen Pontus Gourdon Lisbeth Birk Møller Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease Scientific Reports |
author_facet |
Tina Skjørringe Per Amstrup Pedersen Sidsel Salling Thorborg Poul Nissen Pontus Gourdon Lisbeth Birk Møller |
author_sort |
Tina Skjørringe |
title |
Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease |
title_short |
Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease |
title_full |
Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease |
title_fullStr |
Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease |
title_full_unstemmed |
Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease |
title_sort |
characterization of atp7a missense mutants suggests a correlation between intracellular trafficking and severity of menkes disease |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-04-01 |
description |
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 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. |
url |
https://doi.org/10.1038/s41598-017-00618-6 |
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