STUDIES ON MCCUNE/ALBRIGHT SYNDROME

麦库尼/奥尔布赖特综合征的研究

• 批准号: 6105456
• 负责人: ALLEN M. SPIEGEL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6105456
• 关键词: G protein; biological signal transduction; bone development disorder; developmental genetics; endocrine disorder; gene expression; gene mutation; genetic disorder; genetically modified animals; human genetic material tag; human tissue; laboratory mouse; molecular cloning; molecular pathology; orphan disease /drug; pigmentation disorders; syndrome; tissue /cell culture; tissue mosaicism

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.

McCune-Albright综合征（MAS）是一种 一种非遗传性疾病，其中受影响的受试者表现出各种 看似无关的异常，包括多骨纤维性 发育不良、色素性皮肤病变（黑素斑），以及 各种内分泌器官的自主性功能亢进，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， 肥胖症/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谜，但猜测 都集中在信号传导的缺陷上， 内分泌机能亢进皮肤病变的分布也 这表明，早期获得的体细胞突变的可能性， 胚胎发生和只影响细胞的一个子集（镶嵌现象）。 既然G蛋白突变可以合理解释内分泌 表现，我们搜索并发现了 GS-α基因，其导致Gs蛋白的组成性激活。 这些突变被发现呈镶嵌分布;值得注意的是， 突变基因在正常出现的部分是检测不到的， 内分泌腺，但存在于杂合子水平， 内分泌组织的肿瘤部分。突变型GS-α也是 在发育不良的骨病变中检测到，无论是在多骨症， “经典”形式的MAS和“形式fruste”的疾病， 单骨纤维异常增生突变型GS-α的出现， 心脏和肝脏等器官表明， “非经典”表现，包括猝死。我们的研究 表明MAS是由Gs-alpha的体细胞突变引起的， 在发育早期出现的基因，存在于嵌合体中 分布疾病的更多局灶性表现，如 单骨型骨纤维异常增殖症可能是由 Gs-alpha基因在发育后期出现。来定义 骨发育不良病变的发病机制，我们已经追求 研究在原代培养的细胞从骨病变的患者， MAS。后者已被克隆到不同的种群中， 突变阳性和突变阴性细胞，并已用于 体外研究和裸鼠模型中的体内研究， 与人类骨细胞（与P. Robey，NIDR合作）。后者 当突变的细胞被激活时， 植入的这些研究应该有助于确定治疗方法 最终可能会用于病人身上。