Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Institut für Medizinische Physik und Biophysik, Group Protein X-ray Crystallography and Signal Transduction, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
J Clin Endocrinol Metab. 2019 Apr 1;104(4):1079-1089. doi: 10.1210/jc.2018-01250.
The α subunit of the stimulatory G protein (Gαs) links numerous receptors to adenylyl cyclase. Gαs, encoded by GNAS, is expressed predominantly from the maternal allele in certain tissues. Thus, maternal heterozygous loss-of-function mutations cause hormonal resistance, as in pseudohypoparathyroidism type Ia, whereas somatic gain-of-function mutations cause hormone-independent endocrine stimulation, as in McCune-Albright syndrome.
We report two unrelated boys presenting with a new combination of clinical findings that suggest both gain and loss of Gαs function.
Clinical features were studied and sequencing of GNAS was performed. Signaling capacities of wild-type and mutant Gαs were determined in the presence of different G protein-coupled receptors (GPCRs) under basal and agonist-stimulated conditions.
Both unrelated patients presented with unexplained hyponatremia in infancy, followed by severe early onset gonadotrophin-independent precocious puberty and skeletal abnormalities. An identical heterozygous de novo variant (c.1136T>G; p.F376V) was found on the maternal GNAS allele in both patients; this resulted in a clinical phenotype that differed from known Gαs-related diseases and suggested gain of function at the vasopressin 2 receptor (V2R) and lutropin/choriogonadotropin receptor (LHCGR), yet increased serum PTH concentrations indicative of impaired proximal tubular PTH1 receptor (PTH1R) function. In vitro studies demonstrated that Gαs-F376V enhanced ligand-independent signaling at the PTH1R, LHCGR, and V2R and, at the same time, blunted ligand-dependent responses. Structural homology modeling suggested mutation-induced modifications at the C-terminal α5 helix of Gαs that are relevant for interaction with GPCRs and signal transduction.
The Gαs p.F376V mutation causes a previously unrecognized multisystem disorder.
刺激型 G 蛋白（Gαs）的α亚单位将许多受体与腺苷酸环化酶连接起来。Gαs 由 GNAS 编码，在某些组织中主要从母本等位基因表达。因此，母系杂合性失活突变导致激素抵抗，如假性甲状旁腺功能减退症 1a 型，而体细胞获得性功能突变导致激素非依赖性内分泌刺激，如 McCune-Albright 综合征。
我们报告了两个无关的男孩，他们表现出一种新的组合临床发现，提示 Gαs 功能的获得和丧失。
研究了临床特征，并对 GNAS 进行了测序。在基础和激动剂刺激条件下，在不同的 G 蛋白偶联受体（GPCR）存在下，测定了野生型和突变型 Gαs 的信号转导能力。
两个无关的患者在婴儿期均表现为不明原因的低钠血症，随后出现严重的早期发病的促性腺激素非依赖性性早熟和骨骼异常。在两名患者的母系 GNAS 等位基因上均发现了相同的杂合性新生突变（c.1136T>G；p.F376V）；这导致了一种不同于已知 Gαs 相关疾病的临床表型，提示在抗利尿激素 2 受体（V2R）和促黄体生成素/绒毛膜促性腺激素受体（LHCGR）上获得功能，但血清甲状旁腺素（PTH）浓度升高表明近端肾小管 PTH1 受体（PTH1R）功能受损。体外研究表明，Gαs-F376V 增强了 PTH1R、LHCGR 和 V2R 的配体非依赖性信号转导，同时减弱了配体依赖性反应。结构同源建模提示突变诱导的 Gαs C 末端α5 螺旋的修饰与 GPCR 相互作用和信号转导有关。
Gαs p.F376V 突变导致了一种以前未被认识的多系统疾病。
