假性甲状旁腺功能减退症的分子及临床表型机制研究

Pseudohypoparathyroidism(PHP) is a group of endocrine diseases characterized by hypocalcemia, hyperphosphatemia and parathyroid hormone resistance. Due to the rarity, the pathogenesis of PHP is still unclear. Traditional molecular classification can not accurately reflect the genotype-phenotype relationship,while quite a number of patients could not be classified according to this criterion. Furthermore, PTH also plays a role in bone microstructure, glycolipid metabolism and cardiovascular system, but the related researches are limited and the specific mechanism is not yet clear in PHP patients. Based on our current database including more than 120 cases of PHP, our project intends to establish a larger sample of PHP patients cohort, acquire their gene mutation and methylation spectrum by professional detection methods including MS-MLPA, COBRA, Long-range PCR, the first and second generation gene sequencing, genome sequencing and methylation detection, and to seek for the precise molecular mechanism of PHP. Besides, clinical complications of PHP including bone structural and mechanical changes, glycolipid disorders and cardiovascular events which have been seldomly studied would also be evaluated in our study, in order to establish a more accurate genotype-phenotype relationship, which will contribute to the establishment of more optional clinical treatment goals. Combined these together, we hope to find out a new classification method and develop clinical therapeutic targets of PHP for reference in our country.

假性甲状旁腺功能减退症（PHP）是一组以低血钙、高血磷及甲状旁腺激素（PTH）抵抗为特征的内分泌系统罕见疾病，发病机制不全清楚。目前采用的传统分子分型方法无法对相当比例的患者分型且无法准确反映基因型-表型关系。此外，PTH对于骨微结构、糖脂代谢及心血管系统也有一定作用，但具体机制尚未明确。本研究将在前期研究的基础上，进一步建立大样本PHP患者队列（已有120余例），通过MS-MLPA、COBRA、Long-range PCR、基因测序、甲基化检测及全基因组测序等较为全面的分子诊断手段，获取PHP患者基因突变谱及甲基化谱，对其进行精准的分子分型；评价PHP患者骨骼结构及力学改变、糖脂代谢特点、心血管事件发生风险及并探讨可能作用机制，结合临床特点探索基因型-表型的关联性及有效治疗方法，为寻找适应我国国情的PHP新分类方法及制定临床治疗目标提供参考。

假性甲状旁腺功能减退症（PHP）是一组以低血钙、高血磷及甲状旁腺激素（PTH）抵抗为特征的内分泌系统罕见疾病，发病机制不全清楚。目前采用的传统分子分型方法无法对相当比例的患者分型且无法准确反映基因型-表型关系。此外，PTH对于骨微结构、糖脂代谢及心血管系统也有一定作用，但具体机制尚未明确。本研究在前期研究的基础上，进一步扩大了PHP患者队列，通过MS-MLPA、Sanger测序、及全外显子测序等较为全面的分子诊断手段，对其进行精准的分子分型，发现了新的导致PHP的基因突变，完善了PHP患者基因突变谱及甲基化谱，应用无创的高分辨外周定量CT（HR-pQCT）方法评价了PHP患者中骨微结构的变化和骨强度特性，通过糖脂代谢指标测定及脂肪因子水平检测，描述PHP患者糖脂代谢特点，完善PHP患者心功能水平，并结合临床指标进行心血管事件风险的评估，同时评估了PHP患者妊娠及产后钙稳态变化，以期结合临床特点探索基因型-表型的关联性及有效治疗方法，为寻找适应我国国情的PHP新分类方法及制定临床治疗目标提供参考。