Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty.
Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty.
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DOI：
10.1111/jcmm.13146
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发表时间：
2017-10
影响因子：
5.3
通讯作者：
Ogata T
中科院分区：
文献类型：
--
作者：
Fukami M;Suzuki E;Izumi Y;Torii T;Narumi S;Igarashi M;Miyado M;Katsumi M;Fujisawa Y;Nakabayashi K;Hata K;Umezawa A;Matsubara Y;Yamauchi J;Ogata T
人类基因组编码约750个G蛋白偶联受体（GPCR），包括参与性成熟调节的前动力蛋白受体2（PROKR 2）。先前报道的致病性GPCR基因功能获得突变总是编码具有过度信号转导活性的异常受体。尽管体外试验表明，当与野生型蛋白共转染时，人工产生的PROKR 2失活突变体产生了矛盾的功能获得效应，但在体内尚未观察到这种现象。在这里，我们报告了一个3.5岁的中枢性性早熟女孩中发现的PROKR 2杂合移码突变。突变体mRNA逃脱了无义介导的衰变，并产生了缺乏两个跨膜结构域和羧基末端尾的GPCR。突变体蛋白没有体外信号转导活性;然而，共表达突变体和野生型PROKR 2的细胞表现出明显夸大的配体诱导的Ca 2+反应。结果表明，某些失活的PROKR 2突变体可以通过增强共存野生型蛋白的功能特性而导致青春期提前。考虑到GPCR之间的结构相似性，这种矛盾的功能获得机制可能是各种人类疾病的基础。
The human genome encodes ~750 G‐protein‐coupled receptors (GPCRs), including prokineticin receptor 2 (PROKR2) involved in the regulation of sexual maturation. Previously reported pathogenic gain‐of‐function mutations of GPCR genes invariably encoded aberrant receptors with excessive signal transduction activity. Although in vitro assays demonstrated that an artificially created inactive mutant of PROKR2 exerted paradoxical gain‐of‐function effects when co‐transfected with wild‐type proteins, such a phenomenon has not been observed in vivo. Here, we report a heterozygous frameshift mutation of PROKR2 identified in a 3.5‐year‐old girl with central precocious puberty. The mutant mRNA escaped nonsense‐mediated decay and generated a GPCR lacking two transmembrane domains and the carboxyl‐terminal tail. The mutant protein had no in vitro signal transduction activity; however, cells co‐expressing the mutant and wild‐type PROKR2 exhibited markedly exaggerated ligand‐induced Ca2+ responses. The results indicate that certain inactive PROKR2 mutants can cause early puberty by enhancing the functional property of coexisting wild‐type proteins. Considering the structural similarity among GPCRs, this paradoxical gain‐of‐function mechanism may underlie various human disorders.
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DOI：
10.1016/s0167-4781(02)00546-8
发表时间：
2002-12-12
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Soga, T;Matsumoto, SI;Furuichi, K
通讯作者：
Furuichi, K
影响因子：
8
作者：
Marsango, Sara;di Patti, Maria Carmela Bonaccorsi;Miele, Rossella
通讯作者：
Miele, Rossella
影响因子：
9.8
作者：
Miraoui, Hichem;Dwyer, Andrew A.;Pitteloud, Nelly
通讯作者：
Pitteloud, Nelly
影响因子：
4
作者：
Ma, Lan;Pei, Gang
通讯作者：
Pei, Gang
影响因子：
5.8
作者：
Cole, Lindsay W.;Sidis, Yisrael;Pitteloud, Nelly
通讯作者：
Pitteloud, Nelly