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- Title
Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.
- Authors
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
- 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 ?, ?, ? and ? 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 ? 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.
- Subjects
HYPERCALCEMIA; GENETIC mutation; TYROSINE; COATED vesicles; PROTEIN binding; CELLULAR signal transduction; CALCIUM in the body; G protein-coupled receptor kinases; ENDOCYTOSIS
- Publication
Nature Genetics, 2013, Vol 45, Issue 1, p93
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2492