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Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3
M Andrew Nesbit1, Fadil M Hannan, Sarah A Howles
1Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Nature Genetics
|December 11, 2012
Summary
Mutations in the AP2S1 gene, encoding a subunit of adaptor protein-2 (AP2), cause familial hypocalciuric hypercalcemia type 3 (FHH3). This discovery reveals a novel role for AP2 in regulating calcium homeostasis.
Area of Science:
- Cell Biology
- Endocrinology
- Genetics
Background:
- Adaptor protein-2 (AP2) is crucial for clathrin-mediated endocytosis, a process involved in internalizing membrane proteins like G protein-coupled receptors (GPCRs).
- AP2 links clathrin to vesicle membranes and recognizes specific protein motifs on cargo.
Purpose of the Study:
- To investigate the genetic basis of familial hypocalciuric hypercalcemia type 3 (FHH3), an disorder of calcium homeostasis.
- To identify novel genes and pathways involved in calcium regulation.
Main Methods:
- Genetic analysis of patients with FHH without CASR mutations.
- Functional studies in cells expressing mutated AP2S1 and the calcium-sensing receptor (CaSR).
- Assessment of cellular calcium sensitivity and receptor endocytosis.
Main Results:
- Missense mutations in AP2S1 (encoding the AP2 σ subunit) were identified in over 20% of FHH cases lacking CASR mutations.
- These AP2S1 mutations impair the interaction with CaSR dileucine-based motifs, reducing CaSR endocytosis and cellular calcium sensitivity.
- Disruption of this interaction also affected intracellular signaling pathways.
Conclusions:
- AP2S1 mutations are a significant cause of FHH3, highlighting a new role for AP2 in extracellular calcium homeostasis.
- The findings implicate AP2-mediated endocytosis of CaSR in the regulation of calcium balance.
- This study expands our understanding of the molecular mechanisms underlying calcium disorders.
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