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， 受试者表现出各种看似无关的异常，包括 多发性骨化性纤维异常增殖症、色素性皮损、咖啡色斑点)、 以及包括性腺在内的各种内分泌器官的自主功能亢进， 垂体前叶、甲状腺和肾上腺皮质。内分泌 异常导致性早熟、巨人症、甲状腺功能亢进症和 皮质醇过多症。造成这种零星疾病的原因完全是 令人费解，但人们的猜测集中在信号的缺陷上 转导导致内分泌功能亢进。皮肤的分布 损伤也表明了获得性体细胞突变的可能性 在胚胎发育早期，只影响一小部分细胞(嵌合体)。 因为G蛋白突变可以合理地解释内分泌 表现，我们搜索并发现了Gs-α基因的突变 这会导致Gs蛋白的结构性激活。这些突变 呈镶嵌分布；值得注意的是，突变基因是检测不到的 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。我们的 研究表明，MAS是由Gs-α的体细胞突变引起的 在发育早期发现的基因，呈马赛克分布。

McCune-Albright syndrome (MAS) is a non-genetic disorder in which affected subjects show a variety of seemingly unrelated abnormalities including 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 has been completely enigmatic, but speculations have 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 subset-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. 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.