XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gsα), is paternally expressed. The significance of XLαs in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non-sense variant c.424G>T (p. G142*) in the first exon of XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, while possibly having no significant effects on other gene products of this locus. Ellsworth-Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XLαs failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa-B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.

中文翻译：

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一名患有低磷血症和骨质疏松症的成年患者的XLαs第一个外显子的父系遗传无义变异体c.424G> T（p.G142 *）。

XLαs是刺激性鸟嘌呤核苷酸结合蛋白（Gsα）的α亚基的超大型同工型，在父系中表达。XLαs在人类中的重要性仍然未知。在这里，我们报告了一名患者，该患者出现了骨量增加，低磷血症和甲状旁腺激素（PTH）水平升高。他的血清钙在正常范围的下限。该受试者的整个外显子组测序在XLαs的第一个外显子中发现了一个新的无义变异体c.424G> T（p。G142 *），该变异体是从他父亲那里继承而来的，并传播给了他的女儿。预测该变体仅影响XLα的表达，同时可能对该基因座的其他基因产物没有显着影响。Ellsworth-Howard试验显示先证者对PTH的肾脏反应正常。转染了突变体XLαs的人SaOS2细胞在PTH刺激下未能产生环状单磷酸腺苷，表明对该激素具有骨骼抵抗力。该受试者显示出较高的循环硬化素，dickkopf1和骨保护素（OPG）水平，而核因子kappa-B配体/ OPG比率的受体活化剂较低，从而导致骨吸收降低。我们的发现表明XLαs在骨代谢中起着关键作用，GNAS基因座应被视为高骨量的候选基因。