Stephanie B. Seminara, M.D., Sophie Messager, Ph.D., Emmanouella E. Chatzidaki, B.Sc., Rosemary R. Thresher, Ph.D., James S. Acierno, Jr., B.S., Jenna K. Shagoury, B.S., Yousef Bo-Abbas, M.D., Wendy Kuohung, M.D., Kristine M. Schwinof, M.A., Alan G. Hendrick, Ph.D., Dirk Zahn, Ph.D., John Dixon, B.A., Ursula B. Kaiser, M.D., Susan A. Slaugenhaupt, Ph.D., James F. Gusella, Ph.D., Stephen O'Rahilly, M.D., Mark B.L. Carlton, Ph.D., William F. Crowley, Jr., M.D., Samuel A.J.R. Aparicio, B.M., B.Ch., Ph.D., and William H. Colledge, Ph.D.
Background Puberty, a complex biologic process involving sexualdevelopment, accelerated linear growth, and adrenal maturation,is initiated when gonadotropin-releasing hormone begins to besecreted by the hypothalamus. We conducted studies in humansand mice to identify the genetic factors that determine theonset of puberty.
Methods We used complementary genetic approaches in humans andin mice. A consanguineous family with members who lacked pubertaldevelopment (idiopathic hypogonadotropic hypogonadism) was examinedfor mutations in a candidate gene, GPR54, which encodes a Gprotein–coupled receptor. Functional differences betweenwild-type and mutant GPR54 were examined in vitro. In parallel,a Gpr54-deficient mouse model was created and phenotyped. Responsivenessto exogenous gonadotropin-releasing hormone was assessed inboth the humans and the mice.
Results Affected patients in the index pedigree were homozygousfor an L148S mutation in GPR54, and an unrelated proband withidiopathic hypogonadotropic hypogonadism was determined to havetwo separate mutations, R331X and X399R. The in vitro transfectionof COS-7 cells with mutant constructs demonstrated a significantlydecreased accumulation of inositol phosphate. The patient carryingthe compound heterozygous mutations (R331X and X399R) had attenuatedsecretion of endogenous gonadotropin-releasing hormone and aleft-shifted dose–response curve for gonadotropin-releasinghormone as compared with six patients who had idiopathic hypogonadotropichypogonadism without GPR54 mutations. The Gpr54–deficientmice had isolated hypogonadotropic hypogonadism (small testesin male mice and a delay in vaginal opening and an absence offollicular maturation in female mice), but they showed responsivenessto both exogenous gonadotropins and gonadotropin-releasing hormoneand had normal levels of gonadotropin-releasing hormone in thehypothalamus.
Conclusions Mutations in GPR54, a G protein–coupled receptorgene, cause autosomal recessive idiopathic hypogonadotropichypogonadism in humans and mice, suggesting that this receptoris essential for normal gonadotropin-releasing hormone physiologyand for puberty.
Source Information
From the Reproductive Endocrine Unit (S.B.S., J.S.A., J.K.S., K.M.S., W.F.C.) and the Molecular Neurogenetics Unit, Center for Human Genetic Research (S.A.S., J.F.G.), Massachusetts General Hospital; the Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (W.K., U.B.K.); and the Harvard Institute of Human Genetics, Harvard Medical School (S.A.S., J.F.G.) — all in Boston; Paradigm Therapeutics (S.M., R.R.T., A.G.H., D.Z., J.D., M.B.L.C., S.A.J.R.A, W.H.C.); the Departments of Physiology (E.E.C., W.H.C.), Oncology (S.A.J.R.A.), and Clinical Biochemistry (S.O.) and the Cambridge Institute for Medical Research, Addenbrooke's Hospital (S.O.), University of Cambridge, Cambridge, United Kingdom; and the Faculty of Medicine, Kuwait University, Al-Jabriyah (Y.B.-A.). Drs. Seminara, Messager, Chatzidaki, and Thresher contributed equally to the article. Drs. Crowley, Aparicio, and Colledge were the senior authors.
Address reprint requests to Dr. Colledge at whc23{at}cam.ac.uk; to Dr. Aparicio at Paradigm Therapeutics, 214 Cambridge Science Park, Milton Rd., Cambridge CB4 0WA, United Kingdom, or at saparicio{at}paradigm-therapeutics.com; or to Dr. Crowley at the Reproductive Endocrine Unit, BHX 505, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, or at crowley.william{at}mgh.harvard.edu.
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