ArticleNature genetics2013
Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3.
Article in Nature genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers, 1 of them a synthesis that pooled it.
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Who cites it
120 citing papers in PubMed, 1 synthesis or guideline pooled it, 283 citations in OpenAlex.
- Genetic variants of calcium and vitamin D metabolism in kidney stone disease.Nature communications · 2019Pooled it
- Cinacalcet therapy in symptomatic 11-year-old girl with familial hypocalciuric hypercalcemia type 3.Pediatric nephrology (Berlin, Germany) · 2026Article
- Markedly elevated bone mineral density in genetically elusive familial hypocalciuric hypercalcemia: A case report with targeted genetic analysis of eight candidate genes.Bone reports · 2026Article
- Clinical and molecular characterization of familial hypocalciuric hypercalcemia in an endocrine practice: a case series of 25 patients.JBMR plus · 2026Article
- Multi-faceted roles of β-arrestins in G protein-coupled receptor endocytosis.Nature communications · 2025Article
- Genetic variants predisposing to an increased risk of kidney stone disease.The Journal of clinical investigation · 2025Article
- A calcium-sensing receptor dileucine motif directs internalization to spatially distinct endosomal signaling pathways.iScience · 2025Article
- Measuring Calcium-Sensing Receptor Agonist-Driven Insertional Signaling (ADIS) and Trafficking by TIRF Microscopy.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Monitoring Calcium-Sensing Receptor (CaSR)-Induced Intracellular Calcium Flux Using an Indo-1 Flow Cytometry Assay.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Successful Treatment With Evocalcet Against Familial Hypocalciuric Hypercalcemia Type 3 (FHH3) Identified byCase reports in endocrinology · 2025Article
- Familial states of primary hyperparathyroidism: an update.Journal of endocrinological investigation · 2024Review
- Molecular regulation of calcium-sensing receptor (CaSR)-mediated signaling.Chronic diseases and translational medicine · 2024Review
- AP2A2 mutation and defective endocytosis in a Malian family with hereditary spastic paraplegia.Neurobiology of disease · 2024Article
- Mapping the global interactome of the ARF family reveals spatial organization in cellular signaling pathways.Journal of cell science · 2024Article
- The adaptor protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows.iScience · 2024Article
- Gα11 deficiency increases fibroblast growth factor 23 levels in a mouse model of familial hypocalciuric hypercalcemia.JCI insight · 2024Article
- Genetics of hereditary forms of primary hyperparathyroidism.Hormones (Athens, Greece) · 2024Review
- Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1.The Journal of clinical endocrinology and metabolism · 2024Article
- Challenges in molecular diagnosis of multiple endocrine neoplasia.Frontiers in endocrinology · 2024Review
- Genetic profile of a large Spanish cohort with hypercalcemia.Frontiers in endocrinology · 2024Article
60 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
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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