AP2S1 – Familial Hypocalciuric Hypercalcemia Type 3

Familial hypocalciuric hypercalcemia type 3 (FHH3) is an autosomal dominant disorder characterized by mild to moderate hypercalcemia with relative hypocalciuria and inappropriately normal-to-elevated parathyroid hormone levels. The causative gene, AP2S1, encodes the adaptor protein-2 sigma subunit (AP2σ) involved in clathrin-mediated endocytosis of the calcium‐sensing receptor (CaSR). Impaired AP2σ function disrupts CaSR internalization and signaling, leading to altered calcium homeostasis.

Genetic Evidence

Multiple independent probands harbor heterozygous missense mutations at codon 15 of AP2S1. A Japanese infant presented with de novo c.44G>T (p.Arg15Leu) and hypercalcemia with paradoxical hypercalciuria initially, corrected by low‐calcium formula (PMID:24081735). A 21-year-old woman with hypocalciuria, reduced bone mineral density and developmental disorder also carried c.44G>T (p.Arg15Leu) and responded to evocalcet (PMID:39949382). In a Danish cohort, two of 33 CASR-negative FHH patients had AP2S1 p.Arg15Leu and p.Arg15His with familial segregation confirmed (PMID:27913609). No other AP2S1 variants outside Arg15 have been reported in FHH3.

Segregation

Family screening in the Danish study confirmed co-segregation of AP2S1 Arg15 variants with hypercalcemia in two kindreds (PMID:27913609).

Functional Evidence

In vitro assays demonstrate that AP2σ Arg15 mutations impair AP2 complex assembly and CaSR endocytosis, reducing receptor signaling sensitivity. CRISPR/Cas9 Ap2s1^+/L15^ mice recapitulate FHH3 biochemistry—marked hypercalcemia, hypophosphatemia and hypermagnesemia—while homozygous mutants are embryonic lethal (PMID:33729479). Treatment with cinacalcet or evocalcet normalizes calcium levels in patients and mice by allosteric activation of CaSR.

Conflicting Evidence

No gain-of-function AP2S1 mutations were detected in 19 hypocalcemic patients, arguing against an ADH3 phenotype (PMID:24708097).

Integration & Clinical Utility

Heterozygous AP2S1 Arg15 variants cause FHH3 through a haploinsufficiency mechanism impairing CaSR trafficking. Genetic testing for AP2S1, particularly codon 15 hotspots, is essential to distinguish FHH3 from primary hyperparathyroidism and guide management. CaSR modulators, such as evocalcet and cinacalcet, offer targeted therapy.

Key Take-home: AP2S1 testing is recommended in patients with unexplained hypercalcemia and hypocalciuria to confirm FHH3, prevent unnecessary surgery, and enable personalized calcimimetic treatment.

References

• The Journal of clinical endocrinology and metabolism | 2013 | Identification of AP2S1 mutation and effects of low calcium formula in an infant with hypercalcemia and hypercalciuria. PMID:24081735
• Case Reports in Endocrinology | 2025 | Successful Treatment With Evocalcet Against Familial Hypocalciuric Hypercalcemia Type 3 (FHH3) Identified by AP2S1 Gene Mutation (p.Arg15Leu). PMID:39949382
• European Journal of Endocrinology | 2017 | AP2S1 and GNA11 mutations - not a common cause of familial hypocalciuric hypercalcemia. PMID:27913609
• Human Molecular Genetics | 2021 | Ap2s1 mutation causes hypercalcaemia in mice and impairs interaction between calcium-sensing receptor and adaptor protein-2. PMID:33729479
• The Journal of clinical endocrinology and metabolism | 2014 | Mutational analysis of the adaptor protein 2 sigma subunit (AP2S1) gene: search for autosomal dominant hypocalcemia type 3 (ADH3). PMID:24708097

Evidence Based Scoring (AI generated)