STUDIES ON MCCUNE-ALBRIGHT SYNDROME

McCune-Albright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纤维异常增生三联征，色素沉着 皮肤病变（皮肤白斑）和各种自主性功能亢进 内分泌器官，包括性腺、垂体前叶、甲状腺和肾上腺 皮层 内分泌异常会导致性早熟，发育迟缓， 甲状腺机能亢进和皮质醇增多症 这种偶发性疾病的原因 完全是个谜，但猜测集中在一个缺陷上， 导致内分泌功能亢进 的 皮肤病变的分布也表明了 体细胞突变在胚胎发生早期获得，只影响一个 细胞亚群（镶嵌现象）。 因为G蛋白突变可能 解释内分泌的表现，我们寻找并发现了 导致Gs-α基因的组成性激活， 蛋白 这些突变被发现呈镶嵌分布;值得注意的是， 突变基因在内分泌正常的部分是检测不到的， 腺体，但在肿瘤部分的杂合水平存在， 内分泌组织 在发育不良的骨中也检测到突变型GS-α 病变 在心脏和肝脏等器官中发生突变型Gs-alpha 表明在“非经典”表现中可能起作用，包括突发性 死亡 我们的研究表明，MAS是由体细胞突变引起的， GS-α基因在发育早期出现并在嵌合体中发现 分布

McCune-Albright syndrome (MAS) is a non-inherited disorder in which affected subjects show a variety of seemingly unrelated abnormalities including 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 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. 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.