Elucidetion of pathogeness of derangements in Calcinm metabolism

钙敏感受体(CaSR)是G蛋白偶联受体的一员，被认为是调节甲状旁腺激素(PTH)分泌的重要分子。细胞外钙通过CaSR抑制甲状旁腺素的分泌，血钙与甲状旁腺素的分泌之间存在严格的负反馈系统。已知CaSR基因杂合失活突变可导致以相对低钙尿和轻度高钙血症为特征的家族性低钙尿性高钙血症(FHH)，而CaSR杂合激活突变可导致常染色体显性遗传低钙血症(ADH)并伴有相对高钙尿和PTH缺乏性低钙血症。然而，尽管FHH的临床特征与原发性甲状旁腺功能亢进症患者相似，但FHH患者甲状旁腺的组织学尚未见报道，甲状旁腺功能亢进症是高钙血症的典型原因。此外，AMD患者的详细临床特征也尚不清楚。通过检测CaSR基因突变和分析突变型CaSR的体外功能特性，我们证明FHH患者的甲状旁腺表现出明显的组织学特征，称为脂肪增生，这与原发性甲状旁腺功能亢进症患者不同。此外，我们还发现，一些严重激活的CaSR突变通过抑制Henle粗大升支的肾外髓质钾通道而导致Barter样综合征。这些结果表明CaSR基因突变引起的临床表现的多样性，似乎有助于建立基于分子机制的钙代谢紊乱的新分类。

Calcium-sensing receptor (CaSR) is a member of G protein-coupled receptors that has been identified as a essential molecular for regulating secretion of parathyroid hormone (PTH). Extracellular Ca inhibits secretion of PTH through CaSR and there is a strict negative feedback system between serum Ca and PTH secretion. It has been already known that heterozygous inactivating mutations of CaSR result in familial hypocalciuric hypercalcemia (FHH) characterized by relative hypocalciuria and mild hypercalcemia, whereas heterozygous activating mutations of CaSR cause autosomal dominant hypocalcemia (ADH) with relative hypercalciuria and PTH-deficient hypocalcemia. However, the histology of parathyroid glands in patients with FHH has not been reported although clinical features of FHH are similar to those of patients with primary hyperparathyroidism, which is the typical cause of hypercalcemia. In addition, detailed clinical features of patients with AMD have been unknown, either. By examining mutations in CaSR gene and analyzing functional properties of mutant CaSRs in vitro, we have demonstrated that parathyroid glands in patients with FHH show distinct histological features called lipohyperplasia, which are different from those of patients with primary hyperparathyroidism. In addition, we have shown that some activating mutations of CaSR with severe activation cause Bartter-like syndrome by inhibiting renal outer medullary potassium channel in thick ascending limb of Henle. These results indicate the variability of clinical manifestations caused by mutations in CaSR gene and seem to have contributed to the establishment of the new classification of derangements in calcium metabolism based on molecular mechanisms.