| Title: |
Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3 |
| Authors: |
Nesbit, M; Hannan, F; Howles, SA; Reed, A; Cranston, T; Thakker, C; Gregory, L; Rimmer, A; Rust, N; Graham, U; Morrison, P; Hunter, S; Whyte, M; Mcvean, G; Buck, D; Thakker, R |
| Publication Year: |
2016 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis, which internalizes plasma membrane constituents such as G protein-coupled receptors (GPCRs). AP2, a heterotetramer of α, β, μ and σ subunits, links clathrin to vesicle membranes and binds to tyrosine- and dileucine-based motifs of membrane-associated cargo proteins. Here we show that missense mutations of AP2 σ subunit (AP2S1) affecting Arg15, which forms key contacts with dileucine-based motifs of CCV cargo proteins, result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular calcium homeostasis disorder affecting the parathyroids, kidneys and bone. We found AP2S1 mutations in >20% of cases of FHH without mutations in calcium-sensing GPCR (CASR), which cause FHH1. AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular calcium and reduced CaSR endocytosis, probably through loss of interaction with a C-terminal CaSR dileucine-based motif, whose disruption also decreased intracellular signaling. Thus, our results identify a new role for AP2 in extracellular calcium homeostasis. © 2013 Nature America, Inc. All rights reserved. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
https://doi.org/10.1038/ng.2492 |
| DOI: |
10.1038/ng.2492 |
| Availability: |
https://doi.org/10.1038/ng.2492; https://ora.ox.ac.uk/objects/uuid:7aebc560-02f0-4775-913d-6370f96ec0c0 |
| Rights: |
info:eu-repo/semantics/embargoedAccess |
| Accession Number: |
edsbas.2E29F3FF |
| Database: |
BASE |