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 包括多发性骨质增生性纤维结构不良、色素性皮肤病变(CAFE-AU- 莱特斑)，以及各种内分泌器官的自主功能亢进 包括性腺、垂体前叶、甲状腺和肾上腺皮质。这个 内分泌异常导致性早熟，巨人症/肢端肥大症， 甲状腺机能亢进症和皮质醇增多症。造成这种零星现象的原因 混乱一直是个谜，但人们的猜测集中在一个缺陷上 在导致内分泌功能亢进的信号转导中。这个 皮损的分布也表明有可能 在胚胎发育早期获得的体细胞突变，仅影响 细胞子集(嵌合体)。因为G蛋白突变很可能 解释内分泌表现，我们搜索并发现了突变 导致Gs的结构性激活的Gs-α基因的 蛋白。这些突变是在镶嵌分布中发现的；值得注意的是， 突变基因在内分泌的正常部分未被检测到 腺体，但在肿瘤部分以杂合子水平存在 内分泌组织。在发育不良的骨骼中也检测到了突变的Gs-α 多发性骨质疏松症，MAS的“经典”形式和“形式”的损害 单纯性纤维异常增生症。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。更多 本病的局灶性表现，如单纯性纤维结构不良 可能是由于后来发生的Gs-α基因的体细胞突变所致 正在开发中。

McCune-Albright syndrome (MAS) is an 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/acromegaly, hyperthyroidism, and hypercortisolism. The cause of this sporadic disorder has been 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 as present at heterozygous levels in neoplastic portions of endocrine tissue. Mutant Gs-alpha was also detected in dysplastic bone lesions, both in the polyostotic, "classical" form of MAS and in a "form fruste" of the disease, monostotic fibrous dysplasia. 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. More focal manifestations of the disease such as monostotic fibrous dysplasia may be caused by somatic mutation of the Gs-alpha gene occurring later in development.