Biocruces Bizkaia Health Research Institute, CIBERDEM, CIBERER, Barakaldo, Spain.
Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain.
Eur J Endocrinol. 2019 Jan 1;180(1):59-70. doi: 10.1530/EJE-18-0129.
Objective Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described. Methods The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing. Results Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median: 11.3 mg/dL) but normal or abnormally high parathyroid hormone (PTH) levels (median: 52 pg/mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from eight families. These patients had a median serum calcium level of 7.4 mg/dL and hypoparathyroidism (median: PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium: 10.6 mg/dL; median PTH: 65 pg/mL) with no other alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, p.Lys119Ile, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351Ile, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.Ile816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup). Conclusions Patients with CASR mutations may not fit the classic clinical pictures of hypercalcemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are important for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorders in 82 patients in the study cohort.
目的 分子诊断是钙代谢紊乱的一种有用的诊断工具。钙敏感受体（CaSR）在调节细胞外钙稳态中起着核心作用。我们对 82 个家族的 130 名疑似 CASR 基因突变患者进行了临床、生化和基因特征分析，这是描述此类突变最大的系列之一。
方法 通过聚合酶链反应（PCR）直接测序对 CASR 基因进行突变筛查。
结果 在 26 个家族的 65 名患者中发现了假定的 CaSR 失活突变。这些患者血钙升高（中位数：11.3mg/dL）但甲状旁腺激素（PTH）水平正常或升高（中位数：52pg/mL）。另一方面，在 8 个家族的 17 名患者中发现了假定的 CaSR 激活突变。这些患者血清钙水平中位数为 7.4mg/dL，甲状旁腺功能减退（中位数：PTH 13pg/mL）。此外，在 27 名无其他 CASR 改变但血钙水平升高的患者中发现了先前与高血离子钙水平相关的常见多态性（中位数钙：10.6mg/dL；中位数 PTH：65pg/mL）。总体而言，我们发现了 30 种不同的突变，其中 14 种是以前未报道过的（p.Ala26Ser、p.Cys60Arg、p.Lys119Ile、p.Leu123Met、p.Glu133Val、p.Gly222Glu、p.Phe351Ile、p.Cys542Tyr、p.Cys546Gly、p.Cys677Tyr、p.Ile816Val、p.Ala887Asp、p.Glu934*、p.Pro935_Gln945dup）。
结论 患有 CASR 突变的患者可能不符合高钙血症伴低钙尿或低钙血症伴高钙尿的经典临床特征。分子研究对于确认诊断并将其与其他实体区分开来非常重要。我们的基因分析证实了研究队列中 82 名患者的 CaSR 疾病。
