Study on signal transduction system through calcium-sensing receptor

1.钙敏感受体(CaSR)基因突变失活可导致家族性低钙尿性高钙血症(FHH)和新生儿重度甲状旁腺功能亢进症(NSHPT)，而CaSR激活突变可导致常染色体显性低钙血症(ADH)。NSHPT通常是由CaSR的纯合失活突变引起的，已被认为是致命的，如果在婴儿时期摘除甲状旁腺。我们已经发现了CaSR的新突变，并表明，如果突变的CaSR功能损害轻微，具有CaSR纯合失活突变的患者可以在不进行任何治疗的情况下存活到成年。我们还发现，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。2.人CaSR基因启动子区的克隆除CaSR突变外，该受体的表达异常可能导致钙代谢异常。为了了解CaSR基因表达的调控机制，我们克隆了人CaSR基因的启动子区域。人CaSR基因至少有两个启动子，通过交替作用产生多个mRNAs。在甲状旁腺腺瘤中，由上游启动子驱动的CaSR mRNA的表达水平特异性降低。阐明这些启动子的调控因子对于了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.