Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis
Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis
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DOI：
10.1681/asn.2018121268
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发表时间：
2019-05-01
影响因子：
13.6
通讯作者：
Ogata, Tsutomu
中科院分区：
文献类型：
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作者：
Miyado, Mami;Fukami, Maki;Ogata, Tsutomu
背景：GNAS外显子1-13编码的刺激性G蛋白α亚单位(GNAS-Gsα)介导了包括精氨酸加压素受体2(AVPR2)在内的多种G蛋白偶联受体的信号转导。在假性甲状旁腺功能减退症Ia型和假性甲状旁腺功能减退症中分别发现了母系和父系来源的各种源于种系的GNAS-Gsα变异。已经在McCune-Albright综合征中检测到特定的体细胞功能增益GNAS-Gs阿尔法变体，并可能导致磷酸盐消耗。方法排除AVPR2的一个功能增益变异体，并对其进行功能研究后，我们对两个显性遗传性抗利尿肾病综合征(NSIAD)显著表型的家系进行了全外显子测序。结果全外显子测序发现两个NSIAD候选GNAS-Gsα变异体：一个家系中有两个GNAS-Gsαp.(F68_G70del)，一个家庭中有GNAS-Gsαp.(M255V)。这两个变种都没有出现在公共和内部数据库中。在具有罕见变异的基因中，GNAS-Gsα单独参与AVPR2信号转导，并由这些家族共享。蛋白质结构分析显示，p.M255V-Gsα具有功能增益相容的构象特性，而p.F68_G70del-Gsα则不可能进行这种评估。这两个变异体的功能增益效应都明显低于McCune-Albright综合征特异性躯体Gsα变异体。携带p.F68_G70del-Gsα的模型小鼠表现出正常的生存能力和与NSIAD相容的表型，而携带p.M255V-Gsα的模型小鼠则表现出严重的生存障碍。结论本研究证实了GNAS-Gsα的种系来源的罕见功能增益变异的存在，并导致NSIAD是一种新的Gsα介导的遗传病。AVPR2信号可能对GNAS-Gsα的功能增益效应最为敏感。
Background The stimulatory G-protein alpha-subunit encoded by GNAS exons 1-13 (GNAS-Gs alpha) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gs alpha variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gs alpha variants have been detected in McCune-Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality.Methods We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants.Results Whole-exome sequencing revealed two GNAS-Gs alpha candidate variants for NSIAD: GNAS-Gs alpha p.(F68_G70del) in one family and GNAS-Gs alpha p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gs alpha alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function-compatible conformational property for p.M255V-Gs alpha, although such assessment was not possible for p.F68_G70del-Gs alpha. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gs alpha variants. Model mice for p.F68_G70del-Gs alpha showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gs alpha exhibited severe failure to thrive.Conclusions This study shows that germline-derived gain-of-function rare variants of GNAS-Gs alpha exist and cause NSIAD as a novel Gs alpha-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gs alpha's gain-of-function effects.