STUDIES ON PSEUDOHYPOPARATHYROIDISM AND RELATED DISORDERS

1942年，奥尔布赖特和他的同事描述了一种新的 临床综合征“假性甲状旁腺功能减退症”（PHP）。 患者 他病症不同于那些特发性甲状旁腺功能减退症： 他们表现出典型的宪法特征（奥尔布赖特的 遗传性骨营养不良- AHO），且对外源性 甲状旁腺激素（PTH）。 在最初的报告之后， 缺乏AHO典型躯体特征但耐药的患者 对内源性和施用的PTH的影响。 在PHP中， UcAMP（尿环AMP）在反应中不正常增加 PTH管理。 这表明存在缺陷 激素受体-腺苷酸环化酶复合物。 我们 现在已经表明，许多患有PHP+AHO（PHP Ia）的患者显示出 Gs活性降低约50%（刺激性 腺苷酸相关鸟嘌呤核苷酸结合蛋白 环化酶）。 Gs缺乏症 这可能解释了对多种激素的抵抗， 患者 无AHO的PHP患者Gs活性正常 (PHP Ib）和仅对PTH耐药，以及初步研究 提示这些患者存在PTH受体缺陷。 罕见患者， PHP和AHO及多种激素抵抗显示正常Gs 活动 使用克隆的人Gs α亚基cDNA探针，我们现在 发现受试者成纤维细胞的稳态mRNA水平 与正常相比，PHP Ia减少了约50%。 基因组克隆和其他分子生物学方法正在 用于定义导致Gs的遗传异常 PHP的缺陷

In 1942 Albright and his associates described the features of a new clinical syndrome "pseudohypoparathyroidism" (PHP). Patients with his disorder differ from those with idiopathic hypoparathyroidism: they show characteristic constitutional features (Albright's hereditary osteodystrophy - AHO) and do not respond to exogenous parathyroid hormone (PTH). Subsequent to the original report, patients lacking the typical somatic features of AHO but resistant to endogenous and administrated PTH have been described. In PHP, UcAMP (urinary cyclic AMP) does not increase normally in response to PTH administration. This indicated that there is a defective hormone receptor-adenylate cyclase complex in this disorder. We have now shown that many patients with PHP+AHO (PHP Ia) show an approximately 50% reduction in activity of Gs (the stimulatory guanine nucleotide binding protein associated with adenylate cyclase) in membranes from multiple tissues. Gs deficiency presumably accounts for resistance to multiple hormones in such patients. Patients with PHP without AHO show normal Gs activity (PHP Ib) and resistance only to PTH, and preliminary studies suggest a PTH receptor defect in such patients. Rare patients with PHP and AHO and multiple hormone resistance show normal Gs activity. Using cloned human cDNA probes for the alpha subunit of Gs, we now find that steady state mRNA levels from fibroblasts of subjects with PHP Ia are reduced by approximately 50% compared with normals. Genomic cloning and other molecular biologic approaches are being used to define the genetic abnormality responsible for Gs deficiency in PHP Ia.