The GPR54 gene as a regulator of puberty.
BACKGROUND
Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty.


METHODS
We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein-coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice.


RESULTS
Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotropic hypogonadism was determined to have two separate mutations, R331X and X399R. The in vitro transfection of COS-7 cells with mutant constructs demonstrated a significantly decreased accumulation of inositol phosphate. The patient carrying the compound heterozygous mutations (R331X and X399R) had attenuated secretion of endogenous gonadotropin-releasing hormone and a left-shifted dose-response curve for gonadotropin-releasing hormone as compared with six patients who had idiopathic hypogonadotropic hypogonadism without GPR54 mutations. The Gpr54-deficient mice had isolated hypogonadotropic hypogonadism (small testes in male mice and a delay in vaginal opening and an absence of follicular maturation in female mice), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus.


CONCLUSIONS
Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.
Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
Stephanie B
SB
Seminara
Sophie
S
Messager
Emmanouella E
EE
Chatzidaki
Rosemary R
RR
Thresher
James S
JS
Acierno
Jenna K
JK
Shagoury
Yousef
Y
Bo-Abbas
Wendy
W
Kuohung
Kristine M
KM
Schwinof
Alan G
AG
Hendrick
Dirk
D
Zahn
John
J
Dixon
Ursula B
UB
Kaiser
Susan A
SA
Slaugenhaupt
James F
JF
Gusella
Stephen
S
O'Rahilly
Mark B L
MB
Carlton
William F
WF
Crowley
Samuel A J R
SA
Aparicio
William H
WH
Colledge
D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D007987:Gonadotropin-Releasing Hormone / Q000097:blood; D006062:Gonadotropins / Q000097:blood / Q000172:deficiency*; D006066:Gonads / Q000473:pathology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008126:Lod Score; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011627:Puberty / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012741:Sexual Maturation / Q000235:genetics
D006062:Gonadotropins; C118688:KISS1R protein, human; C492248:Kiss1r protein, mouse; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D018013:Receptors, Neuropeptide; D007987:Gonadotropin-Releasing Hormone