Paradoxical gain‐of‐function mutant of the G‐protein‐coupled receptor <scp>PROKR</scp>2 promotes early puberty

Abstract

Abstract The human genome encodes ~750 G‐protein‐coupled receptors ( GPCR s), including prokineticin receptor 2 ( PROKR 2) 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 PROKR 2 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 PROKR 2 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 PROKR 2 exhibited markedly exaggerated ligand‐induced Ca 2+ responses. The results indicate that certain inactive PROKR 2 mutants can cause early puberty by enhancing the functional property of coexisting wild‐type proteins. Considering the structural similarity among GPCR s, this paradoxical gain‐of‐function mechanism may underlie various human disorders.