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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Autores principales:	Tina Skjørringe, Per Amstrup Pedersen, Sidsel Salling Thorborg, Poul Nissen, Pontus Gourdon, Lisbeth Birk Møller
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/31afdcd2171345e18a1b524b05516b28
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spelling	oai:doaj.org-article:31afdcd2171345e18a1b524b05516b282021-12-02T11:52:29ZCharacterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease10.1038/s41598-017-00618-62045-2322https://doaj.org/article/31afdcd2171345e18a1b524b05516b282017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00618-6https://doaj.org/toc/2045-2322Abstract 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.Tina SkjørringePer Amstrup PedersenSidsel Salling ThorborgPoul NissenPontus GourdonLisbeth Birk MøllerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-18 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Tina Skjørringe Per Amstrup Pedersen Sidsel Salling Thorborg Poul Nissen Pontus Gourdon Lisbeth Birk Møller
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 Portfolio
publishDate	2017
url	https://doaj.org/article/31afdcd2171345e18a1b524b05516b28
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Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease

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