STUDIES ON MCCUNE/ALBRIGHT SYNDROME

麦库尼-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多种 看似无关的异常，包括多骨性纤维性异常 发育不良、色素性皮肤病变（牛奶咖啡斑）和 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。的 内分泌异常导致性早熟， 巨人症/肢端肥大症、甲状腺功能亢进症和皮质醇增多症。的 这种散发性疾病的原因一直是个谜，但猜测 集中在信号转导缺陷导致 内分泌功能亢进。皮损的分布也 表明早期获得的体细胞突变的可能性 胚胎发生并仅影响细胞的子集（镶嵌现象）。 由于 G 蛋白突变可以合理地解释内分泌 表现，我们寻找并发现了突变 Gs-α 基因导致 Gs 蛋白的组成型激活。 这些突变被发现呈镶嵌分布；值得注意的是， 在正常出现的部分中检测不到突变基因 内分泌腺，但以杂合水平存在 内分泌组织的肿瘤部分。突变体 Gs-alpha 也被 在发育不良骨病变中检测到，无论是在多骨性、 MAS 的“经典”形式以及该疾病的“形式 fruste”， 单性纤维异常增殖症。突变体 Gs-α 的出现 心脏和肝脏等器官表明可能在 “非典型”表现，包括猝死。我们的研究 表明 MAS 是由 Gs-alpha 体细胞突变引起的 基因出现在发育早期并在嵌合体中发现 分布。该疾病的更多局灶性表现，例如 单性纤维异常增殖症可能是由体细胞突变引起 Gs-alpha 基因出现在发育后期。定义 发育不良骨病变的发病机制，我们一直在追求 来自骨损伤患者的原代培养细胞的研究 马航。后者已被克隆到不同的群体中 突变阳性和突变阴性细胞，并已用于 体外研究和植入裸鼠模型的体内研究 与人类骨细胞（与 P. Robey，NIDR）。后者 概括了突变细胞时的纤维异常增生病变 植入。这些研究应该有助于确定治疗方法 最终可能会用于患者。

McCune-Albright syndrome (MAS) is a non-inherited 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 was 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 occuring later in development. To define the pathogenesis of the dysplastic bone lesions, we have pursued studies in primary cultured cells from bone lesions of patients with MAS. The latter have been cloned into distinct populations of mutant-positive and mutant negative-cells and have been used for in vitro studies, and in vivo studies in a nude mouse model implanted with human bone cells (with P. Robey, NIDR). The latter recapitulates the fibrous dysplasia lesion when mutant cells are implanted. These studies should be useful for identifying treatments that might eventually be used in patients.