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Nat Genet. 2013 Jan;45(1):93-7. doi: 10.1038/ng.2492. Epub 2012 Dec 9.

Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.

Author information

1
Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

Abstract

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.

PMID:
23222959
PMCID:
PMC3605788
DOI:
10.1038/ng.2492
[Indexed for MEDLINE]
Free PMC Article

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