Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone
Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone
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DOI：
10.1359/jbmr.2000.15.1.120
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发表时间：
2000-01-01
影响因子：
6.2
通讯作者：
Robey, PG
中科院分区：
文献类型：
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作者：
Bianco, P;Riminucci, M;Robey, PG
已在McCune-Albright综合征（MAS;特征为多骨纤维性发育不良、咖啡Au lait皮肤色素沉着和内分泌疾病）患者中发现了编码刺激性G蛋白（Gs）α亚基的GNAS 1基因的激活性错义突变。由于骨纤维异常增殖症（FD）也通常发生在典型MAS的背景之外，我们询问是否可以在非MAS FD病变中常规鉴定相同的突变，我们分析了一系列8个随机获得的，连续的非-MAS FD，并通过使用标准引物组扩增基因组DNA产生的cDNA测序和通过使用一种新的、高灵敏度的方法，该方法使用蛋白质核酸（PNA）引物来阻断正常等位基因的扩增。组织学检查结果与MAS相关FD中观察到的结果没有区别，包括归因于过量内源性环磷酸腺苷（cAMP）的细胞形状和胶原质地的细微变化。骨软化变化（未矿化类骨质）在病变FD骨中突出。在体内移植试验中，从FD中分离的基质细胞未能重现正常的听小骨;相反，它们产生了纤维结构不良的微型复制品。这些数据提供了证据，表明先前在FD的个体病例中注意到的GNAS 1突变的发生在非MAS FD中是常见的并且可能是恒定的发现。这些研究结果支持的观点，即FD，MAS，和非骨骼孤立的内分泌病变与GNAS 1突变代表了一个频谱的表型表达（可能反映不同的模式体细胞镶嵌）相同的基础疾病，我们的结论是，机制的基础上发展的FD病变，并希望机制靶向治疗方法的开发，也必须是相同的MAS和非MAS FD。
Activating missense mutations of the GNAS1 gene, encoding the alpha subunit of the stimulatory G protein (Gs), have been identified in patients with the McCune-Albright syndrome (MAS; characterized by polyostotic fibrous dysplasia, cafe au lait skin pigmentation, and endocrine disorders). Because fibrous dysplasia (FD) of bone also commonly occurs outside of the context of typical MAS, we asked whether the same mutations could be identified routinely in non-MAS FD lesions, We analyzed a series of 8 randomly obtained, consecutive cases of non-MAS FD and identified R201 mutations in the GNAS1 gene in all of them by sequencing cDNA generated by amplification of genomic DNA using a standard primer set and by using a novel, highly sensitive method that uses a protein nucleic acid (PNA) primer to block amplification of the normal allele. Histologic findings were not distinguishable from those observed in MAS-related FD and included subtle changes in cell shape and collagen texture putatively ascribed to excess endogenous cyclic adenosine monophosphate (cAMP), Osteomalacic changes (unmineralized osteoid) were prominent in lesional FD bone. In an in vivo transplantation assay, stromal cells isolated from FD failed to recapitulate a normal ossicle; instead, they generated a miniature replica of fibrous dysplasia, These data provide evidence that occurrence of GNAS1 mutations, previously noted in individual cases of FD, is a common and perhaps constant finding in non-MAS FD. These findings support the view that FD, MAS, and nonskeletal isolated endocrine lesions associated with GNAS1 mutations represent a spectrum of phenotypic expressions (likely reflecting different patterns of somatic mosaicism) of the same basic disorder, We conclude that mechanisms underlying the development of the FD lesions, and hopefully mechanism-targeted therapeutic approaches to be developed, must also be the same in MAS and non-MAS FD.