Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty

Maki Fukami, Erina Suzuki, Yoko Izumi, Tomohiro Torii, Satoshi Narumi, Maki Igarashi, Mami Miyado, Momori Katsumi, Yasuko Fujisawa, Kazuhiko Nakabayashi, Kenichiro Hata, Akihiro Umezawa, Yoichi Matsubara, Junji Yamauchi, Tsutomu Ogata

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2623-2626
Number of pages4
JournalJournal of Cellular and Molecular Medicine
Volume21
Issue number10
DOIs
Publication statusPublished - 2017 Oct
Externally publishedYes

Keywords

  • GPCR
  • mutation
  • neuroendocrine

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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