Codon Arg15 Mutations of the AP2S1 Gene: Common Occurrence in Familial Hypocalciuric Hypercalcemia Cases Negative for Calcium-Sensing Receptor (CASR) Mutations

Context: Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder with three known subtypes: FHH1, FHH2, and FHH3. About 65% of FHH cases are FHH1, caused by inactivating mutations of the calcium-sensing receptor (CASR) gene. FHH3 was recently found to be caused by codon Arg15 (p.R15) mutations in the adaptor-related protein complex 2, σ-2 subunit that interacts with the CaSR and is encoded by the AP2S1 gene. Objective: The objective of the study was to assess the prevalence of AP2S1 mutations, and describe the phenotype of FHH3, in an independent cohort of FHH subjects lacking CASR mutations. Patients and Methods: Thirty-nine patients presenting with some combination of hypercalcemia, hypermagnesemia, nonsuppressed serum PTH levels, and reduced urinary calcium excretion were studied. Exon 2 of the AP2S1 gene was PCR amplified from patient genomic DNA and Sanger sequenced. The presence of p.R15 mutations was confirmed by restriction enzyme analysis. Results: Five of the 39 subjects had...