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，患者表现出各种看似无关的异常，包括多发性骨化性纤维异常增殖症、色素性皮肤病变(咖啡色斑点)，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。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。我们证明Gs-α基因突变导致Gs蛋白的结构性激活是MAS的原因。这些体细胞突变以镶嵌分布的形式被发现，并被认为发生在胚胎发生期间；突变基因可能在内分泌腺的正常外观部分检测不到，但在内分泌组织的肿瘤部分存在杂合性水平。突变Gs-α也在发育不良的骨病变中被检测到，无论是在多发性骨质疏松症，经典型的MAS，还是在该病的一种形式，单生性纤维结构不良。突变Gs-α在心脏和肝脏等器官中的出现表明，包括猝死在内的非经典表现可能起到了作用。我们的研究表明，MAS是由Gs-α基因的体细胞突变引起的，该突变发生在发育早期，并呈镶嵌分布。这种疾病的更多局灶性表现，如单纯性纤维发育不良，可能是由于Gs-α基因的体细胞突变发生在发育后期。为了明确发育不良骨损伤的发病机制，我们进行了来自MAS患者骨损伤的原代培养细胞的研究(与P.Robey，NIDCR)。后者已被Robeys团队克隆到不同的突变阳性和突变阴性细胞群体中，并已用于体外研究，以及在裸鼠模型中植入人骨细胞的体内研究。后者在植入突变细胞时重现纤维异常增殖性病变。这些研究应该有助于确定最终可能用于患者的治疗方法。-G蛋白，纤维异常增生，激活突变，Gs-α，嵌合体，骨细胞

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. We showed that mutations of the Gs-alpha gene that lead to constitutive activation of the Gs protein are the cause of MAS. These somatic mutations are found in a mosaic distribution and are thought to occur during embryogenesis; the mutant gene may be undetectable in normal- appearing portions of endocrine glands, but 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 (with P. Robey, NIDCR) in primary cultured cells from bone lesions of patients with MAS. The latter have been cloned by Robeys group 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 . 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. - G Protein, fibrous dysplasia, activating mutation, Gs-alpha, mosaicism, bone cells