GNAS transcripts in skeletal progenitors:: evidence for random asymmetric allelic expression of Gsα
GNAS transcripts in skeletal progenitors:: evidence for random asymmetric allelic expression of Gsα
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DOI：
10.1093/hmg/ddm139
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发表时间：
2007-08-15
影响因子：
3.5
通讯作者：
Riminucci, Mara
中科院分区：
文献类型：
--
作者：
Michienzi, Stefano;Cherman, Natasha;Riminucci, Mara
由位于染色体20 q13上的鸟嘌呤核苷酸结合蛋白α刺激（GNAS）基因座编码的Gs α基因的激活突变是以骨骼病变[骨纤维异常增殖症（FD）]、皮肤外疾病（主要是内分泌功能亢进和皮肤色素沉着过度）及其可变组合[McCune-Albright综合征（MAS）]为特征的不同临床表型的基础。这种临床异质性通常被认为反映了突变的合子后起源。然而，在一些人类出生后组织中的Gs α基因的印记模式表明，父母依赖的表观遗传机制也可能在突变的GNAS基因型的表型效应中发挥作用。FD病变是由突变的克隆性骨祖细胞产生的，这些细胞沿着其正常对应物存在于FD骨髓基质中。我们分析了从一系列信息丰富的FD/MAS患者中分离的正常和突变的克隆形成基质细胞的后代中Gs α和其他GNAS替代转录物的等位基因表达模式。我们在这里报告的第一次，两个Gs α等位基因是不平等的表达在正常和FD突变的基质克隆。然而，与印记相反，Gs α等位基因表达的比率在来自同一患者的不同克隆中随机建立。这一结果表明，在克隆性骨祖细胞中发生了非亲本依赖的Gs α表达调节，并且在单细胞水平上，可能影响FD病变的严重程度。此外，我们发现，正常和突变的克隆形成基质细胞表达GNAS替代转录比常见的Gs α，其中一些可能是相关的FD的发展。
Activating mutations of the Gs alpha gene, encoded by the guanine nucleotide-binding protein, alpha stimulating (GNAS) locus located on chromosome 20q13, underlie different clinical phenotypes characterized by skeletal lesions [fibrous dysplasia (FD) of bone], extraskeletal diseases (mainly endocrine hyperfunction and skin hyperpigmentation) and variable combinations thereof [the McCune-Albright syndrome (MAS)]. This clinical heterogeneity is commonly assumed to reflect the post-zygotic origin of the mutation. However, the pattern of imprinting of the Gs alpha gene in some human post-natal tissues suggests that parental-dependent epigenetic mechanisms may also play a role in the phenotypic effect of the mutated GNAS genotype. FD lesions are generated by mutated clonogenic osteoprogenitors that reside, along with their normal counterparts, in FD bone marrow stroma. We analyzed the allelic expression pattern of Gs alpha and other GNAS alternative transcripts in the progeny of normal and mutated clonogenic stromal cells isolated in vitro from a series of informative FD/MAS patients. We report here for the first time that the two Gs alpha alleles are unequally expressed in both normal and FD-mutated stromal clones. However, in contrast to imprinting, the ratio of Gs alpha allelic expression is randomly established in different clones from the same patient. This result suggests that a parental-independent modulation of Gs alpha expression occurs in clonogenic osteoprogenitor cells and, at the single cell level, may impact on the severity of an FD lesion. Furthermore, we show that normal and mutated clonogenic stromal cells express GNAS alternative transcripts other than the common Gs alpha, some of which may be relevant to the development of FD.