Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
J Cell Mol Med. 2017 Oct;21(10):2623-2626. doi: 10.1111/jcmm.13146. Epub 2017 Mar 24.
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 Ca 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.
人类基因组编码了约 750 个 G 蛋白偶联受体（GPCRs），包括参与性成熟调节的促动力素受体 2（PROKR2）。先前报道的 GPCR 基因突变均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，人工创建的 PROKR2 无活性突变体会产生反常的功能获得效应，但在体内尚未观察到这种现象。在这里，我们报告了一名 3.5 岁女孩出现中枢性性早熟，该女孩携带 PROKR2 的杂合移码突变。突变的 mRNA 逃避了无意义介导的衰变，并产生了缺乏两个跨膜结构域和羧基末端尾巴的 GPCR。该突变蛋白没有体外信号转导活性；然而，共表达突变体和野生型 PROKR2 的细胞表现出明显增强的配体诱导的 Ca 反应。结果表明，某些无活性的 PROKR2 突变体可以通过增强共存野生型蛋白的功能特性来引起性早熟。考虑到 GPCRs 之间的结构相似性，这种反常的功能获得机制可能是各种人类疾病的基础。
