STUDIES ON MCCUNE-ALBRIGHT SYNDROME

McCune-Albright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， 多骨纤维性发育不良、色素性皮肤病变（黑色素斑）， 以及包括性腺在内的各种内分泌器官的自主性功能亢进， 垂体前叶甲状腺和肾上腺皮质 内分泌 异常会导致性早熟、发育迟缓、甲状腺功能亢进， 皮质醇过多症 这种偶发性疾病的原因已经完全 神秘的，但猜测集中在信号缺陷， 转导导致内分泌功能亢进。 皮肤的分布 病变也表明了获得性体细胞突变的可能性， 早期，在胚胎发生中，并且仅影响细胞的子集（镶嵌现象）。 既然G蛋白突变可以合理解释内分泌 表现，我们寻找并发现了Gs-alpha基因的突变 导致Gs蛋白的组成性激活。 这些突变 发现在镶嵌分布;值得注意的是，突变基因是检测不到的 在正常出现的部分内分泌腺，但目前在 内分泌组织的肿瘤部分中的杂合水平。 我们 研究表明，MAS是由GS-α的体细胞突变引起的， 在发育早期出现的基因，以嵌合体形式分布。

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.