Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 21, Issue 10, Pages 2623-2626Publisher
WILEY
DOI: 10.1111/jcmm.13146
Keywords
GPCR; mutation; neuroendocrine
Categories
Funding
- Japan Society for the Promotion of Science
- National Center for Child Health and Development
- Takeda Foundation
- Ministry of Health, Labour and Welfare
- Japan Agency for Medical Research and Development
- National Center Biobank Network
- Grants-in-Aid for Scientific Research [17K10074, 16K09979] Funding Source: KAKEN
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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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