Hendy Geoffrey N, Canaff Lucie, Newfield Ron S, Tripto-Shkolnik Liana, Wong Betty Y L, Lee Bonnie S P, Cole David E C
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.
J Clin Endocrinol Metab. 2014 Jul;99(7):E1311-5. doi: 10.1210/jc.2014-1120. Epub 2014 Apr 14.
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.
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.
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.
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.
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.
家族性低钙血症性高钙血症（FHH）是一种常染色体显性疾病，有三种已知亚型：FHH1、FHH2和FHH3。约65%的FHH病例为FHH1，由钙敏感受体（CASR）基因的失活突变引起。最近发现FHH3是由衔接蛋白相关蛋白复合物2的σ-2亚基中的密码子Arg15（p.R15）突变引起的，该亚基与CaSR相互作用，由AP2S1基因编码。
本研究的目的是评估在一组无CASR突变的FHH受试者独立队列中AP2S1突变的患病率，并描述FHH3的表型。
对39例出现高钙血症、高镁血症、血清甲状旁腺激素水平未受抑制和尿钙排泄减少等某种组合症状的患者进行了研究。从患者基因组DNA中PCR扩增AP2S1基因的外显子2并进行Sanger测序。通过限制性酶切分析确认p.R15突变的存在。
39名受试者中有5名存在AP2S1 p.R15突变，频率为13%。先前报道的三种复发性突变在我们的队列中均有发现（两名患者为p.R15C，两名患者为p.R15L，一名患者为p.R15H）。由于CASR突变导致的FHH3表型与FHH1的表型没有实质性差异。
结果证实，大量疑似患有FHH但经证实CASR突变阴性的患者存在AP2S1 p.R15突变。鉴于FHH1中CASR筛查已显示出临床益处（避免不必要的甲状旁腺切除术），在此类病例中应考虑筛查AP2S1 p.R15突变。
