Research on signal transduction through parathyroid hormone(PTH)/PTH-related protein receptor

1. PTH/PTH相关蛋白（PTHrP）受体的表达调控为了阐明PTH/PTHrP受体的表达调控机制，我们克隆并分析了人PTH/PTHrP受体基因的5′区。结果表明，人PTH/PTHrP受体基因至少有2个启动子和3个5'-未翻译外显子。其中一种启动子是肾脏特有的，另一种启动子广泛应用于许多组织（Fukumoto S et al ., 1997）。假性甲状旁腺功能减退症（ibd）患者PTH/PTHrP受体基因的评估假性甲状旁腺功能减退症是一种以PTH抵抗为特征的异质性疾病复合体。b型假性甲状旁腺功能减退一直被认为是由PTH/PTHrP受体异常引起的。然而，我们之前的研究结果显示，这些患者的PTH/PTHrP受体cDNA未见异常（J clinical Endocrinol Metab 81: 2554,1996）。因此，我们下一步研究PTH/PTHrP受体在这些患者中表达的调控机制是否异常。然而，8例Ib型假性甲状旁腺功能低下患者的启动子区和5'-未翻译外显子未见异常。结合最近发现Ib型假性甲状旁腺功能减退症的相关基因不在PTH/PTHrP受体位点，PTH/PTHrP受体失活突变导致Bromstrand软骨发育不良，我们认为Ib型假性甲状旁腺功能减退症不是由PTH/PTHrP受体异常引起的。PTH/PTHrP受体信号转导的研究PTH/PTHrP受体的信号转导不仅受其表达的调节，还受其配体的产生和分泌动力学的调节。甲状旁腺钙敏感受体在调节甲状旁腺激素分泌中起关键作用。我们分析了几例甲状旁腺激素分泌异常患者的钙敏感受体基因，发现了该受体基因的新突变。

1. Regulation of expression of PTH/PTH-related protein (PTHrP) receptorIn order to clarify the regulatory mechanisms of the expression of PTH/PTHrP receptor, we have cloned and analyzed 5'-region of human PTH/PTHrP receptor gene. The results indicate that human PTH/PTHrP receptor gene has at least two promoters and three 5'-untranslated exons. One of these promoters is specific for kidney, and the other promoter is widely used in many tissues (Fukumoto S et al, 1997).2. Evaluation of PTH/PTHrP receptor gene in patients with pseudohypoparathyroidism type IbPseudohypoparathyroidism is a heterogenous disease complex characterized by resistance to PTH.Pseudohypoparathyroidism type Ib had been thought to be caused by abnormal PTH/PTHrP receptor. However, previous our results showed that there is no abnormality in cDNA for PTH/PTHrP receptor in these patients (J Clin Endocrinol Metab 81 : 2554,1996). Therefore, we next investigated if the regulatory mechanisms of the expression of PTH/PTHrP receptor is abnormal in these patients. However, promoter regions and 5'-untranslated exons in 8 patients with pseudohypoparathyroidism type Ib showed no abnormality. Together with the recent findings that the responsible gene for pseudohypoparathyroidism type Ib is not located in PTH/PTHrP receptor locus and inactivating mutations of PTH/PTHrP receptor result in Bromstrand chondrodysplasia, it is concluded that pseudohypoparathyroidism type Ib is not caused by abnormal PTH/PTHrP receptor.3. Study on signal transduction through PTH/PTHrP receptorSignal transduction through PTH/PTHrP receptor is modulated not only by its expression, but also by the production and secretion dynamics of its ligand. Parathyroid calcium-sensing receptor plays pivotal roles in the regulation of PTH secretion. We have analyzed calcium-sensing receptor gene in several patients with abnormal PTH secretion, and found novel mutations in this receptor gene.