Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3

MA Nesbit, FM Hannan, SA Howles, AAC Reed… - Nature …, 2013 - nature.com
MA Nesbit, FM Hannan, SA Howles, AAC Reed, T Cranston, CE Thakker, L Gregory…
Nature genetics, 2013nature.com
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 …
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.
nature.com