Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner.
Maternal GNAS Contributes to the Extra-Large G Protein α-Subunit (XLαs) Expression in a Cell Type-Specific Manner.
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DOI：
10.3389/fgene.2021.680537
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发表时间：
2021
影响因子：
3.7
通讯作者：
Bastepe M
中科院分区：
文献类型：
--
作者：
Cui Q;Aksu C;Ay B;Remillard CE;Plagge A;Gardezi M;Dunlap M;Gerstenfeld LC;He Q;Bastepe M
GNAS编码刺激性G蛋白α亚基（Gsα）及其大变体XLαs。研究表明XLαs仅在父系表达。因此，XLαs缺陷被认为是导致父系GNAS突变患者某些结果的原因，如假性-假性甲状旁腺功能减退症，以及与20号染色体母系单亲二体性相关的表型，其中包括GNAS。然而，对骨髓基质细胞（BMSC）的研究表明XLαs可以双等位基因表达。影响Gsα和XLαs的组成性激活GNAS突变导致的BMSC异常分化是骨纤维异常增殖症的潜在病理学。为了研究等位基因XLαs的表达，我们采用了下一代测序和XLαs和Gsα共有的多态性，以及A/B，另一种父系表达的GNAS转录本。在小鼠BMSCs中，Gsα转录物为48.4 ± 0.3%的父系转录物，而A/B为99.8 ± 0.2%的父系转录物。相比之下，XLαs的表达在不同样本中不同，父源贡献范围为43.0%至99.9%。在骨骼（83.7-99.6%）和小脑（83.8 - 100%）中也检测到父亲XLαs表达的样本间差异，但在培养的颅骨成骨细胞（99.1 ± 0.1%）中未检测到。BMSC的成骨分化使父源XLαs表达从基线时的83.9 ± 1.5%变为97.2 ± 1.1%。在骨诱导条件下生长的两个人BMSC样品中，XLαs表达也主要是单等位基因（91.3或99.6%）。因此，母体GNAS显著促进BMSC中XLαs的表达，而不是成骨细胞。因此，XLαs活性的改变可能发生在某些细胞类型中，无论GNAS缺陷的亲本来源如何。
GNAS encodes the stimulatory G protein alpha-subunit (Gsα) and its large variant XLαs. Studies have suggested that XLαs is expressed exclusively paternally. Thus, XLαs deficiency is considered to be responsible for certain findings in patients with paternal GNAS mutations, such as pseudo-pseudohypoparathyroidism, and the phenotypes associated with maternal uniparental disomy of chromosome 20, which comprises GNAS. However, a study of bone marrow stromal cells (BMSC) suggested that XLαs could be biallelically expressed. Aberrant BMSC differentiation due to constitutively activating GNAS mutations affecting both Gsα and XLαs is the underlying pathology in fibrous dysplasia of bone. To investigate allelic XLαs expression, we employed next-generation sequencing and a polymorphism common to XLαs and Gsα, as well as A/B, another paternally expressed GNAS transcript. In mouse BMSCs, Gsα transcripts were 48.4 ± 0.3% paternal, while A/B was 99.8 ± 0.2% paternal. In contrast, XLαs expression varied among different samples, paternal contribution ranging from 43.0 to 99.9%. Sample-to-sample variation in paternal XLαs expression was also detected in bone (83.7–99.6%) and cerebellum (83.8 to 100%) but not in cultured calvarial osteoblasts (99.1 ± 0.1%). Osteoblastic differentiation of BMSCs shifted the paternal XLαs expression from 83.9 ± 1.5% at baseline to 97.2 ± 1.1%. In two human BMSC samples grown under osteoinductive conditions, XLαs expression was also predominantly monoallelic (91.3 or 99.6%). Thus, the maternal GNAS contributes significantly to XLαs expression in BMSCs but not osteoblasts. Altered XLαs activity may thus occur in certain cell types irrespective of the parental origin of a GNAS defect.
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