Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations.

[familial hypocalciuric hypercalcemia]

Familial hypocalciuric hypercalcemia (FHH ) is an autosomal dominant disorder with three known subtypes : FHH 1 , FHH 2 , and FHH 3 . About 65 % of FHH cases are FHH 1 , caused by inactivating mutations of the calcium-sensing receptor (CASR ) gene . FHH 3 was recently found to be caused by codon Arg 15 (p .R 15 ) mutations in the adaptor-related protein complex 2 , Ïƒ-2 subunit that interacts with the CaSR and is encoded by the AP 2 S 1 gene .T he objective of the study was to assess the prevalence of AP 2 S 1 mutations , and describe the phenotype of FHH 3 , in an independent cohort of FHH subjects lacking CASR mutations .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 AP 2 S 1 gene was PCR amplified from patient genomic DNA and Sanger sequenced . The presence of p .R 15 mutations was confirmed by restriction enzyme analysis .Five of the 39 subjects had AP 2 S 1 p .R 15 mutations , a frequency of 13 %. The three recurrent mutations reported previously were all found in our cohort (p .R 15 C in two , p .R 15 L in two , and p .R 15 H in one subject ). The FHH 3 phenotype did not differ materially from that of FHH 1 due to CASR mutations .T he results affirm that a significant number of patients suspected of having FHH but proven negative for CASR mutation have AP 2 S 1 p .R 15 mutations . Screening for AP 2 S 1 p .R 15 mutations in such cases should be considered , given the clinical benefits (avoiding unnecessary parathyroidectomy ) that have already been demonstrated for CASR screening in FHH 1 .

Diseases
Validation

Diseases presenting "calcium excretion" symptom

adrenal incidentaloma

aromatase deficiency

familial hypocalciuric hypercalcemia

kabuki syndrome

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