Paradoxical gain-of-function mutant of the G-protein-coupled receptor PROKR2 promotes early puberty.
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.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Maki
0000-0001-9971-4035
M
Fukami
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Erina
E
Suzuki
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Yoko
Y
Izumi
Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Tomohiro
T
Torii
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Satoshi
S
Narumi
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Maki
M
Igarashi
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Mami
M
Miyado
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Momori
M
Katsumi
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Yasuko
Y
Fujisawa
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kazuhiko
K
Nakabayashi
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kenichiro
K
Hata
Department of Reproductive Biology, Center for Regenerative Medicine, National Institute for Child Health and Development, Tokyo, Japan.
Akihiro
A
Umezawa
National Research Institute for Child Health and Development, Tokyo, Japan.
Yoichi
Y
Matsubara
Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan.
Junji
J
Yamauchi
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Tsutomu
T
Ogata
D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D000073659:Gain of Function Mutation; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D011629:Puberty, Precocious / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion
C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide
GPCR; mutation; neuroendocrine