Study on signal transduction system through calcium-sensing receptor

1.钙敏感受体（CaSR）突变的研究CaSR失活突变导致家族性低钙性高钙血症（FHH）和新生儿严重甲状旁腺功能亢进症（NSHPT），而CaSR激活突变导致常染色体显性低钙血症（ADH）。NSHPT通常由CaSR的纯合失活突变引起，如果在婴儿期切除甲状旁腺，则NSHPT是致命的。我们已经发现了新的CaSR突变，并表明如果突变CaSR的功能损伤是轻微的，CaSR纯合失活突变患者可以不经任何治疗存活到成年。我们也发现CaSR失活突变患者的甲状旁腺组织学表现与原发性甲状旁腺功能亢进症患者不同。人CaSR基因启动子区克隆除CaSR基因突变外，该受体表达紊乱可能导致Ca代谢异常。为了了解CaSR表达的调控机制，我们克隆了人类CaSR基因的启动子区域。人类CaSR基因至少有两个启动子，通过交替应用产生多个mrna。由上游启动子驱动的CaSR mRNA表达水平在甲状旁腺瘤中特异性降低。阐明这些启动子的调控因子对于理解钙代谢紊乱的发病机制是必要的。

1.Study on mutations of calcium-sensing receptor(CaSR)Inactivating mutations of CaSR cause familial hypocalciuric hypercalcemia(FHH)and neonatal severe hyperparathyroidism(NSHPT), while activating mutations of CaSR result in autosomal dominant hypocalcemia(ADH). NSHPT is usually caused by homozygous inactivating mutations of CaSR and has been proposed to be fatal if parathyroid glands were removed during infancy. We have identified novel mutations of CaSR and shown that the patient with homozygous inactivating mutation of CaSR can survive into adulthood without any treatment, if the functional impairment of the mutant CaSR is mild. We have also shown that histological appearance of parathyroid glands in patients with inactivating mutations of CaSR is different from that in patients with primary hyperparathyroidism.2.Cloning of promoter region of human CaSR geneIn addition to mutations of CaSR, derangements of expression of this receptor may result in abnormal Ca metabolism. In order to understand the regulatory mechanisms for expression of CaSR, we have cloned promoter region of human CaSR gene. Human CaSR gene has at lease two promoters and produces multiple mRNAs by alternate aplicing. Expression levels of CaSR mRNA driven by the upstream promoter were specifically reduced in parathyroid adenomas. Elucidation of regulatory factors of these promtoers is necessary for understanding pathogenesis of derangements of Ca metabolism.