Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.
Nat Genet
; 45(1): 93-7, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-23222959
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, ß, 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Complexo 2 de Proteínas Adaptadoras
/
Subunidades sigma do Complexo de Proteínas Adaptadoras
/
Hipercalcemia
/
Mutação
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article