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发育不良三联征，色素沉着 皮肤病变（皮肤白斑）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 青春期发育迟缓甲状腺机能亢进和皮质醇增多症 事业 这种零星的疾病完全是个谜， 集中在信号传导的缺陷导致内分泌 机能亢进 皮肤病变的分布也表明 在胚胎发生早期获得体细胞突变的可能性， 只影响细胞的一个亚单位（镶嵌现象）。 因为G蛋白 突变可以合理地解释内分泌表现，我们 寻找并发现了Gs-alpha基因的突变 Gs蛋白的组成性激活。 这些突变被发现 在嵌合分布中;值得注意是，突变基因在 内分泌腺的正常外观部分，但存在于 内分泌组织的肿瘤部分中的杂合水平。 突变体 在发育不良的骨病变中也检测到GS-α。 发生 心脏和肝脏等器官中的突变型Gs-alpha表明， 在“非经典”的表现，包括猝死。 我们的研究 表明MAS是由Gs-alpha基因的体细胞突变引起的 在发育的早期出现，呈镶嵌分布。

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.