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 临床表现为假性甲状旁腺功能减退症(Php)。患有疾病的患者 他的疾病与特发性甲状旁腺功能减退症不同： 他们表现出独特的体质特征(奥尔布赖特的 遗传性骨营养不良(HHO)，对外源性激素无反应 甲状旁腺素(PTH)。在最初的报告之后， 缺乏典型AHO躯体特征但有抵抗力的患者 对内源性甲状旁腺激素和给药甲状旁腺素已有描述。在PHP中， UcAMP(尿环磷酸腺苷)未正常升高 致甲状旁腺素管理。这表明有一个缺陷 激素受体-腺苷环化酶复合体在这种疾病中的作用。我们 现在已经表明，许多患有PHP+Aho(PHIa)的患者表现出 Gs活性降低约50%(刺激性 腺苷酸鸟嘌呤核苷酸结合蛋白 来自多个组织的膜)。GS缺乏症 可能是对多种激素产生抵抗力的原因 病人。无AHO的PHP患者Gs活动正常 (PHIb)和仅对PTH的抗性，以及初步研究 提示此类患者存在甲状旁腺素受体缺陷。罕见的患者患有 PHP和AHO和多激素抵抗显示正常 活动。 使用克隆的人Gsα亚单位的cdna探针，我们现在 研究发现受试者成纤维细胞的稳态mRNA水平 与正常相比，PHIa减少了大约50%。 基因组克隆和其他分子生物学方法正在进行中 用来定义引起气肿的基因异常 PHIa缺乏症。

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.