The GNAS locus is an imprinted site. The α-subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation.

中文翻译：

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GNAS 基因突变影响 XLα 和骨骼健康：长期被忽视的关系

GNAS 基因座是一个印记位点。刺激性 G 蛋白的 α 亚基 (Gsα) 和超大变体 (XLαs) 是 GNAS 基因座的两个重要产物。Gsα 的异常表达与假性甲状旁腺功能减退症 (PHP) 和相关疾病相关，包括奥尔布赖特遗传性骨营养不良 (AHO)、假性假性甲状旁腺功能减退症 (PPHP) 和进行性骨发育不良 (POH)。XLαs 蛋白可以模拟 Gsα 响应甲状旁腺激素 (PTH) 刺激而催化细胞内合成环磷酸腺苷 (cAMP)，这可能参与父系 GNAS 缺陷患者 PPHP 和 POH 的发病机制。成年患者XLα第一个外显子中父系遗传的无义变异可能与骨折和骨硬化症相关。GNAS 基因座的XLαs产物与骨重塑之间的关系可能被忽视了。在这里，我们总结了XLαs变异的遗传小鼠模型的表型和临床病例，并提示XLαs的异常父系表达可能与POH的发生有关，并影响成骨细胞和破骨细胞的分化。