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Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3

Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis which internalises plasma membrane constituents such as G protein-coupled receptors (GPCRs)(1-3) . AP2, a heterotetramer of alpha, beta, mu and sigma subunits, links clathrin...

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Autores principales: Nesbit, M. Andrew, Hannan, Fadil M., Howles, Sarah A., Reed, Anita A.C., Cranston, Treena, Thakker, Clare E., Gregory, Lorna, Rimmer, Andrew J., Rust, Nigel, Graham, Una, Morrison, Patrick J., Hunter, Steven J., Whyte, Michael P., McVean, Gil, Buck, David, Thakker, Rajesh V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605788/
https://www.ncbi.nlm.nih.gov/pubmed/23222959
http://dx.doi.org/10.1038/ng.2492
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author Nesbit, M. Andrew
Hannan, Fadil M.
Howles, Sarah A.
Reed, Anita A.C.
Cranston, Treena
Thakker, Clare E.
Gregory, Lorna
Rimmer, Andrew J.
Rust, Nigel
Graham, Una
Morrison, Patrick J.
Hunter, Steven J.
Whyte, Michael P.
McVean, Gil
Buck, David
Thakker, Rajesh V.
author_facet Nesbit, M. Andrew
Hannan, Fadil M.
Howles, Sarah A.
Reed, Anita A.C.
Cranston, Treena
Thakker, Clare E.
Gregory, Lorna
Rimmer, Andrew J.
Rust, Nigel
Graham, Una
Morrison, Patrick J.
Hunter, Steven J.
Whyte, Michael P.
McVean, Gil
Buck, David
Thakker, Rajesh V.
author_sort Nesbit, M. Andrew
collection PubMed
description Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis which internalises plasma membrane constituents such as G protein-coupled receptors (GPCRs)(1-3) . AP2, a heterotetramer of alpha, beta, mu and sigma subunits, links clathrin to vesicle membranes and binds to tyrosine-based and dileucine-based motifs of membrane-associated cargo proteins(1,4). Here, we show that AP2 sigma subunit (AP2S1) missense mutations, which all involved the Arg15 residue (Arg15Cys, Arg15His and Arg15Leu) that forms key contacts with dileucine-based motifs of CCV cargo proteins(4), result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular-calcium homeostasis disorder affecting parathyroids, kidneys and bone(5-7) These AP2S1 mutations occurred in >20% of FHH patients without calcium-sensing GPCR (CaSR) mutations which cause FHH1(8-12). AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular-calcium and reduced CaSR endocytosis, likely through a loss of interaction with a C-terminus CaSR dileucine-based motif whose disruption also decreased intracellular signalling. Thus, our results reveal a new role for AP2 in extracellular-calcium homeostasis.
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spelling pubmed-36057882013-07-01 Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3 Nesbit, M. Andrew Hannan, Fadil M. Howles, Sarah A. Reed, Anita A.C. Cranston, Treena Thakker, Clare E. Gregory, Lorna Rimmer, Andrew J. Rust, Nigel Graham, Una Morrison, Patrick J. Hunter, Steven J. Whyte, Michael P. McVean, Gil Buck, David Thakker, Rajesh V. Nat Genet Article Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis which internalises plasma membrane constituents such as G protein-coupled receptors (GPCRs)(1-3) . AP2, a heterotetramer of alpha, beta, mu and sigma subunits, links clathrin to vesicle membranes and binds to tyrosine-based and dileucine-based motifs of membrane-associated cargo proteins(1,4). Here, we show that AP2 sigma subunit (AP2S1) missense mutations, which all involved the Arg15 residue (Arg15Cys, Arg15His and Arg15Leu) that forms key contacts with dileucine-based motifs of CCV cargo proteins(4), result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular-calcium homeostasis disorder affecting parathyroids, kidneys and bone(5-7) These AP2S1 mutations occurred in >20% of FHH patients without calcium-sensing GPCR (CaSR) mutations which cause FHH1(8-12). AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular-calcium and reduced CaSR endocytosis, likely through a loss of interaction with a C-terminus CaSR dileucine-based motif whose disruption also decreased intracellular signalling. Thus, our results reveal a new role for AP2 in extracellular-calcium homeostasis. 2012-12-09 2013-01 /pmc/articles/PMC3605788/ /pubmed/23222959 http://dx.doi.org/10.1038/ng.2492 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Nesbit, M. Andrew
Hannan, Fadil M.
Howles, Sarah A.
Reed, Anita A.C.
Cranston, Treena
Thakker, Clare E.
Gregory, Lorna
Rimmer, Andrew J.
Rust, Nigel
Graham, Una
Morrison, Patrick J.
Hunter, Steven J.
Whyte, Michael P.
McVean, Gil
Buck, David
Thakker, Rajesh V.
Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3
title Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3
title_full Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3
title_fullStr Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3
title_full_unstemmed Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3
title_short Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3
title_sort mutations in ap2s1 cause familial hypocalciuric hypercalcemia type 3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605788/
https://www.ncbi.nlm.nih.gov/pubmed/23222959
http://dx.doi.org/10.1038/ng.2492
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