PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Ga-protein leads to biased signaling
PROKR2 mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Ga-protein leads to biased signaling
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特发性低促性腺激素性性腺功能减退症中的 PROKR2 突变：选择性破坏与 G 蛋白的结合导致信号传导偏差
DOI：
10.1096/fj.201801575r
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Jia-Da Li
中科院分区：
文献类型：
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作者：
Dan-Na Chen;Yaguang Zhao;Jiayu Wu;Hong Jia;Xinying Wang;Ruizhi Zheng;Fang Jiang;Zhiheng Chen;Jia-Da Li
特发性低促性腺激素性性腺功能减退症（IHH）是一种罕见的疾病，由促性腺激素释放激素的产生、分泌或作用不足引起。前动力蛋白（PROK）受体2（PROKR 2）是IHH的致病基因，编码GPCR PROKR 2。当PROKR 2与其配体PROKs结合时，它可以激活几种信号传导途径，包括IP 3/Ca 2+、MAPK和cAMP途径。然而，中国IHH患者中PROKR 2的突变谱尚未建立。在本研究中，我们发现中国高达13.3%（18/135）的IHH患者携带PROKR 2突变。本研究中的大多数变异是私有的;然而，在10名独立患者中鉴定出aPROKR 2（c.533G > C; p.W178S）突变，这意味着可能的创始者突变。功能研究表明，6个新的PROKR 2突变导致不同程度的信号转导降低。两个IHH相关突变（L218 P和R270 H）破坏了Gαq依赖性信号传导，但维持了正常的Gαs和ERK 1/2信号传导。谷胱甘肽S-转移酶下拉实验表明，R270 H突变破坏了PROKR 2细胞内环3与Gαq蛋白的相互作用，但不破坏Gαs蛋白的相互作用。我们的结果表明，选择性破坏与特定Gα蛋白的相互作用可能是某些IHH相关PROKR 2突变的偏倚信号的基础。赵玉，Wu，J.，Jia，H.，王，X.，Zheng，R.，蒋飞，陈D-N陈志，Li，J. -D.PROKR2mutations in idiopathic hypogonadotropic hypogonadism：selective disruption of the binding to a Gα-protein leads to biased signaling. FASEB J. 33，4538-4546（2019）。www.fasebj.org
Idiopathic hypogonadotropic hypogonadism (IHH) is a rare disorder caused by the deficient production, secretion, or action of gonadotropin‐releasing hormone. Prokineticin (PROK) receptor 2 (PROKR2), a causative gene for IHH, encodes a GPCR PROKR2. When PROKR2 binds to its ligands PROKs, it may activate several signaling pathways, including IP3/Ca2+, MAPK, and cAMP pathways. However, the mutational spectrum ofPROKR2in Chinese patients with IHH has not been established. In the present study, we found that up to 13.3% (18/135) of patients with IHH in China carried mutations inPROKR2. Most of the variants in this study were private; however, aPROKR2(c.533G > C; p.W178S) mutation was identified in 10 independent patients, implying a possible founder mutation. Functional studies indicated that 6 novel PROKR2 mutations led to decreased signaling to various extents. Two IHH‐associated mutations (L218P and R270H) disrupted Gαq‐dependent signaling but maintained normal Gαs and ERK1/2 signaling. A glutathione S‐transferase pull‐down experiment demonstrated that R270H mutation disrupted the interaction of intracellular loop 3 of PROKR2 to Gαq protein but not Gαs protein. Our results indicated that selective disruption of the interaction with a specific Gα‐protein might underlie the biased signaling for certain IHH‐associatedPROKR2mutations.—Zhao, Y., Wu, J., Jia, H., Wang, X., Zheng, R., Jiang, F., Chen, D.‐N., Chen, Z., Li, J.‐D.PROKR2mutations in idiopathic hypogonadotropic hypogonadism: selective disruption of the binding to a Gα‐protein leads to biased signaling. FASEB J. 33, 4538–4546 (2019). www.fasebj.org