A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor
A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor
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DOI：
10.1056/nejm199610103351505
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发表时间：
1996-10-10
影响因子：
158.5
通讯作者：
Thakker, RV
中科院分区：
文献类型：
--
作者：
Pearce, SHS;Williamson, C;Thakker, RV
背景钙敏感受体调节甲状旁腺激素的分泌以响应细胞外钙浓度的变化，导致受体功能丧失的突变与常见的低钙尿高钙血症有关。在两种激酶中，涉及功能获得的突变与低钙血症有关。我们研究的可能性，后一种类型的突变可能会导致一个表型的家族性低钙血症与hypercalciumuria.Methods我们研究了6 kinetamine给予诊断的常染色体显性遗传性甲状旁腺功能减退症的基础上，他们的低钙血症和正常的血清甲状旁腺激素浓度，一个组合，这表明一个缺陷的钙敏感受体。低钙血症与高钙尿症相关，维生素D治疗导致高钙尿症、肾钙质沉着症和肾损害增加。结果在人胚肾细胞系HEK-293中检测到5个钙敏感受体基因胞外区的错义突变（Asn 118 Lys、Phe 128 Leu、Thr 151 Met、Glu 191 Lys和Phe 612 Ser），这些突变与该病共分离。对HEK-293细胞中三种突变受体的功能性表达的分析表明，剂量-反应曲线发生了变化，使得细胞中产生总磷酸肌醇半最大增加所需的细胞外钙浓度显著降低。（P = 0.02至P < 0.001）低于野生型受体所需的水平。敏感受体与家族性低钙血症综合征伴高钙尿症有关，需要与甲状旁腺功能减退症相区别。
Background The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familiar hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria.Methods We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293).Results Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P = 0.02 to P < 0.001) lower than those required for the wild-type receptor.Conclusions Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.