ArticleHuman molecular genetics2015
Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 88 citations in OpenAlex.
- Significantly elevated calcium levels and gallstone disease in a patient with familial hypocalciuric hypercalcaemia.Endocrinology, diabetes & metabolism case reports · 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
- Cinacalcet therapy in symptomatic 11-year-old girl with familial hypocalciuric hypercalcemia type 3.Pediatric nephrology (Berlin, Germany) · 2026Article
- Case report: A Newly Identified G-protein Subunit α-11 Loss-of-Function Variant Causing Familial Hypocalciuric Hypercalcemia Type 2 in an Italian Kindred.Frontiers in endocrinology · 2026Article
- AP2M1 Is a Candidate Gene for Microcephaly and Intellectual Disability in 3q27.1 Deletions.American journal of medical genetics. Part A · 2025Article
- A Hypercalcemic Deception: Uncovering an Unusual Case of Familial Hypocalciuric Hypercalcemia.Cureus · 2025Article
- Bone in Parathyroid Diseases Revisited: Evidence From Epidemiological, Surgical and New Drug Outcomes.Endocrine reviews · 2025Review
- A calcium-sensing receptor dileucine motif directs internalization to spatially distinct endosomal signaling pathways.iScience · 2025Article
- Heritable hyperparathyroidism: Genetic insights and clinical implications.Best practice & research. Clinical endocrinology & metabolism · 2025Review
- Successful Treatment With Evocalcet Against Familial Hypocalciuric Hypercalcemia Type 3 (FHH3) Identified byCase reports in endocrinology · 2025Article
- Habituation learning: insights from zebrafish larvae.Frontiers in molecular neuroscience · 2025Review
- Monitoring Calcium-Sensing Receptor (CaSR)-Induced Intracellular Calcium Flux Using an Indo-1 Flow Cytometry Assay.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Familial states of primary hyperparathyroidism: an update.Journal of endocrinological investigation · 2024Review
- The adaptor protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows.iScience · 2024Article
- Molecular and Clinical Spectrum of Primary Hyperparathyroidism.Endocrine reviews · 2023Article
- GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Article
- Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2022Review
- Genetics of monogenic disorders of calcium and bone metabolism.Clinical endocrinology · 2022Review
- Disorders of the Calcium Sensing Signaling Pathway: From Familial Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.Journal of clinical medicine · 2022Review
- European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.European journal of endocrinology · 2022Article
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Authors and funding
36 authors at 20 institutions in 4 countries.
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Abstract
The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.
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