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Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. | LitMetric

AI Article Synopsis

  • Adaptor protein-2 (AP2) is crucial for clathrin-mediated endocytosis, linking clathrin to vesicle membranes and helping internalize cell membrane components like G protein-coupled receptors (GPCRs).
  • Mutations in the σ subunit of AP2 (AP2S1), particularly affecting Arg15, lead to familial hypocalciuric hypercalcemia type 3 (FHH3), a disorder related to calcium balance in the body.
  • These mutations impair sensitivity and endocytosis of the calcium-sensing receptor (CaSR), indicating that AP2 plays a significant role in regulating extracellular calcium levels.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605788PMC
http://dx.doi.org/10.1038/ng.2492DOI Listing

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