GNAS is one of the most complex gene loci in the human genome and encodes multiple gene products including Gsα, XLαs, NESP55, A/B, and AS transcripts. XLαs, the extra-large G protein ɑ-subunit, is paternally expressed. XLɑs and Gsɑ share the common 2–13 exons with different promoters and first exons. Therefore, XLɑs contains most of the functional domains of Gsα including receptor and effector binding sites. In vitro studies suggest a “Gsɑ”-like function of XLɑs regarding the stimulation of cAMP generation in response to receptor activation with different cellular actions. However, it is unclear whether XLαs has an important physiological function in humans. Pseudopseudohypoparathyroidism (PPHP) and progressive osseous heteroplasia (POH) are caused by paternally inherited mutations of GNAS. Maternal uniparental disomy of chromosome 20 [UPD(20)mat] lacks paternal chromosome 20. Therefore, the phenotypes of these diseases may be secondary to the abnormal functions of XLɑs, at least partly. From the phenotypes of human diseases like PPHP, POH, and UPD(20)mat, as well as some animal models with deficient XLɑs functions, it could be seen that XLɑs is involved in the growth and development of the mammalian fetus, plays a different role in glucose, lipid, and energy metabolism when compared with Gsɑ, and could prevent heterotopic ossification in humans and mice. More in vivo and in vitro studies, especially the development of conditional XLɑs knockout mice, are needed to clarify the physiopathologic roles and related signal pathways of XLɑs.

GNAS是人类基因组中最复杂的基因座之一，编码多种基因产物，包括Gsα，XLα，NESP55，A / B和AS转录本。XLαs是超大的G蛋白γ亚基，在父系中表达。XLɑs和Gsɑ与不同的启动子和第一个外显子共享共同的2-13个外显子。因此，XLɑs包含Gsα的大部分功能域，包括受体和效应子结合位点。体外研究表明，XLɑs具有类似“ Gs-”的功能，可响应不同细胞作用下受体激活而刺激cAMP生成。然而，尚不清楚XLα在人类中是否具有重要的生理功能。假性假性甲状旁腺功能低下（PPHP）和进行性骨异型增生（POH）是由GNAS的父系遗传突变引起的。孕产妇单亲二体性20号染色体[UPD（20）mat]缺少父系20号染色体。因此，这些疾病的表型可能至少部分地是XLɑs异常功能的继发性。从人类疾病的表型，例如PPHP，POH和UPD（20）mat，以及某些XLs功能不足的动物模型，可以看出XLɑs参与了哺乳动物胎儿的生长和发育，起着不同的作用。与Gsɑ相比，在葡萄糖，脂质和能量代谢中起着重要的作用，并且可以防止人和小鼠的异位骨化。需要更多的体内和体外研究，尤其是条件性XLɑs基因敲除小鼠的发育，以阐明XLɑs的生理病理学作用和相关信号途径。