Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.

Journal article

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.

Authors: Nesbit, M; Hannan, F; Howles, SA; Reed, A; Cranston, T

• Publication status: Published
• Journal: Nature genetics
• Volume: 45
• Issue: 1
• Pages: 93-97
• Publication date: 2013-01-01
• DOI: 10.1038/ng.2492
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Male; Adaptor Protein Complex sigma Subunits; Molecular Sequence Data; Adult; Receptors, Calcium-Sensing; Conserved Sequence; Adaptor Protein Complex 2; Hypercalcemia; Protein Conformation; Amino Acid Sequence; Sequence Alignment; Female; Humans; Calcium; Mutation; Models, Molecular