STUDIES ON MCCUNE-ALBRIGHT SYNDROME

麦考恩-奥尔布赖特综合征(MAS)是一种非遗传性疾病 受影响的受试者表现出各种看似无关的异常 包括典型的多发性骨化性纤维异常增殖症三联症，色素沉着 皮肤损害(咖啡馆斑点)和自主性功能亢进 各种内分泌器官，包括性腺、垂体前叶、甲状腺、 和肾上腺皮质。内分泌异常导致性早熟 青春期、巨人症、甲状腺机能亢进症和皮质醇亢进症。的起因 这种零星的疾病完全是谜一样的，人们猜测 集中在导致内分泌的信号转导缺陷上 机能亢进。皮损的分布也表明 胚胎发育早期获得体细胞突变的可能性和 仅影响细胞的一个亚单位(嵌合体)。因为一种G蛋白 突变可以合理地解释内分泌表现，我们 搜索并发现Gs-α基因突变导致 Gs蛋白的结构性激活。这些突变被发现 在镶嵌分布中；值得注意的是，突变基因在 内分泌腺的正常外观部分，但存在于 内分泌组织中肿瘤部分的杂合子水平。突变型 在发育不良的骨组织中也检测到GS-α。发生 心脏和肝脏等器官中的突变Gs-α提示可能的作用 在“非经典”表现中，包括猝死。我们的研究 提示MAS是由Gs-α基因的体细胞突变引起的 发生在发育早期，呈马赛克分布。

McCune-Albright syndrome (MAS) is a non-inherited disorder in which affected subjects show a variety of seemingly unrelated abnormalities include the classic triad of polyostotic fibrous dysplasia, pigmented skin lesions (cafe-au-lait spots), and autonomous hyperfunction of various endocrine organs including gonads, anterior pituitary, thyroid, and adrenal cortex. The endocrine abnormalities lead to precocious puberty, gigantism, hyperthyroidism, and hypercortisolism. The cause of this sporadic disorder had been completely enigmatic, with speculations centered on a defect in signal transduction leading to endocrine hyperfunction. The distribution of skin lesions has also suggested the possibility of a somatic mutation acquired early in embryogenesis and affecting only a subunit of cells (mosaicism). Since a G protein mutation could plausibly explain the endocrine manifestations, we searched for and found mutations of the Gs-alpha gene that lead to constitutive activation of the Gs protein. These mutations were found in a mosaic distribution; notably, mutant gene was undetectable in normal-appearing portions of endocrine glands, but was present at heterozygous levels in neoplastic portions of endocrine tissue. Mutant Gs-alpha was also detected in dysplastic bone lesions. Occurrence of mutant Gs-alpha in organs such as heart and liver suggest a possible role in "non-classical" manifestations, including sudden death. Our studies suggest that MAS is caused by a somatic mutation in the Gs-alpha gene occurring early in development and found in a mosaic distribution.