title: Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations.
abstract: BACKGROUND
  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.
  
  
  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 AP2S1 p.R15 mutations, a frequency of 13%. The three recurrent mutations reported previously were all found in our cohort (p.R15C in two, p.R15L in two, and p.R15H in one subject). The FHH3 phenotype did not differ materially from that of FHH1 due to CASR mutations.
  
  
  CONCLUSIONS
  The results affirm that a significant number of patients suspected of having FHH but proven negative for CASR mutation have AP2S1 p.R15 mutations. Screening for AP2S1 p.R15 mutations in such cases should be considered, given the clinical benefits (avoiding unnecessary parathyroidectomy) that have already been demonstrated for CASR screening in FHH1.
authors.affiliation: Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Calcium Research Laboratory and Hormones and Cancer Research Unit (G.N.H., L.C.), Royal Victoria Hospital, Montreal, Québec, Canada H3A 1A1; Department of Pediatrics (R.S.N.), University of California, San Diego, and Rady Children's Hospital San Diego, San Diego, California 92123; Diabetes and Endocrinology Unit (L.T.-S.), Hillel Yaffe Medical Center, Hadera 38100, Israel; and Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.Y.L.W, B.S.P.L., D.E.C.C.), University of Toronto, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.forename: Ron S
authors.initials: RS
authors.lastname: Newfield
authors.forename: Liana
authors.initials: L
authors.lastname: Tripto-Shkolnik
authors.forename: Betty Y L
authors.initials: BY
authors.lastname: Wong
authors.forename: Bonnie S P
authors.initials: BS
authors.lastname: Lee
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000235:genetics*; D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D002648:Child; D003062:Codon; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D006801:Humans; D006934:Hypercalcemia / Q000151:congenital* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D055815:Young Adult
chemical_list: C510065:AP2S1 protein, human; D033962:Adaptor Protein Complex 2; D034002:Adaptor Protein Complex sigma Subunits; C095550:CASR protein, human; D003062:Codon; D044169:Receptors, Calcium-Sensing; D001120:Arginine