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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(2008). Kisspeptin Is Present in Ovine Hypophysial Portal Blood But Does Not Increase during the Preovulatory Luteinizing Hormone Surge: Evidence that Gonadotropes Are Not Direct Targets of Kisspeptin in Vivo. Endocrinology
149: 1951-1959
[Abstract][Full Text]
Roa, J., Vigo, E., Castellano, J. M., Gaytan, F., Navarro, V. M., Aguilar, E., Dijcks, F. A., Ederveen, A. G. H., Pinilla, L., van Noort, P. I., Tena-Sempere, M.
(2008). Opposite Roles of Estrogen Receptor (ER)-{alpha} and ER{beta} in the Modulation of Luteinizing Hormone Responses to Kisspeptin in the Female Rat: Implications for the Generation of the Preovulatory Surge. Endocrinology
149: 1627-1637
[Abstract][Full Text]
Ebling, F. J. P., Luckman, S. M.
(2008). RFAmide-Related Peptide: Another Sexy Peptide?. Endocrinology
149: 899-901
[Full Text]
Ramachandran, R., Patterson, M., Murphy, K. G., Dhillo, W. S., Patel, S., Kazarian, A., Ghatei, M. A., Bloom, S. R.
(2008). Preanalytical Factors Affecting RIA Measurement of Plasma Kisspeptin. Clin. Chem.
54: 615-617
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Parent, A.-S., Rasier, G., Matagne, V., Lomniczi, A., Lebrethon, M.-C., Gerard, A., Ojeda, S. R., Bourguignon, J.-P.
(2008). Oxytocin Facilitates Female Sexual Maturation through a Glia-to-Neuron Signaling Pathway. Endocrinology
149: 1358-1365
[Abstract][Full Text]
Kinsey-Jones, J. S., Li, X. F., Luckman, S. M., O'Byrne, K. T.
(2008). Effects of Kisspeptin-10 on the Electrophysiological Manifestation of Gonadotropin-Releasing Hormone Pulse Generator Activity in the Female Rat. Endocrinology
149: 1004-1008
[Abstract][Full Text]
Teles, M. G., Bianco, S. D.C., Brito, V. N., Trarbach, E. B., Kuohung, W., Xu, S., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., Latronico, A. C.
(2008). A GPR54-Activating Mutation in a Patient with Central Precocious Puberty. NEJM
358: 709-715
[Abstract][Full Text]
Filby, A. L, Aerle, R. v., Duitman, J., Tyler, C. R
(2008). The Kisspeptin/Gonadotropin-Releasing Hormone Pathway and Molecular Signaling of Puberty in Fish. Biol. Reprod.
78: 278-289
[Abstract][Full Text]
Wagner, G. C., Johnston, J. D., Clarke, I. J., Lincoln, G. A., Hazlerigg, D. G.
(2008). Redefining the Limits of Day Length Responsiveness in a Seasonal Mammal. Endocrinology
149: 32-39
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Nakamura, Y., Aoki, S., Yewei Xing, , Sasano, H., Rainey, W. E.
(2007). Metastin Stimulates Aldosterone Synthesis in Human Adrenal Cells. Reproductive Sciences
14: 836-845
[Abstract]
Quaynor, S., Hu, L., Leung, P. K., Feng, H., Mores, N., Krsmanovic, L. Z., Catt, K. J.
(2007). Expression of a Functional G Protein-Coupled Receptor 54-Kisspeptin Autoregulatory System in Hypothalamic Gonadotropin-Releasing Hormone Neurons. Mol. Endocrinol.
21: 3062-3070
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Goodman, R. L., Lehman, M. N., Smith, J. T., Coolen, L. M., de Oliveira, C. V. R., Jafarzadehshirazi, M. R., Pereira, A., Iqbal, J., Caraty, A., Ciofi, P., Clarke, I. J.
(2007). Kisspeptin Neurons in the Arcuate Nucleus of the Ewe Express Both Dynorphin A and Neurokinin B. Endocrinology
148: 5752-5760
[Abstract][Full Text]
Seminara, S. B.
(2007). Converging at Puberty's Hub. Endocrinology
148: 5145-5146
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Roth, C. L., Mastronardi, C., Lomniczi, A., Wright, H., Cabrera, R., Mungenast, A. E., Heger, S., Jung, H., Dubay, C., Ojeda, S. R.
(2007). Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty. Endocrinology
148: 5147-5161
[Abstract][Full Text]
Caraty, A., Smith, J. T., Lomet, D., Ben Said, S., Morrissey, A., Cognie, J., Doughton, B., Baril, G., Briant, C., Clarke, I. J.
(2007). Kisspeptin Synchronizes Preovulatory Surges in Cyclical Ewes and Causes Ovulation in Seasonally Acyclic Ewes. Endocrinology
148: 5258-5267
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Dungan, H. M., Gottsch, M. L., Zeng, H., Gragerov, A., Bergmann, J. E., Vassilatis, D. K., Clifton, D. K., Steiner, R. A.
(2007). The Role of Kisspeptin GPR54 Signaling in the Tonic Regulation and Surge Release of Gonadotropin-Releasing Hormone/Luteinizing Hormone. J. Neurosci.
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Jameson, J. L.
(2007). Rites of passage through puberty: A complex genetic ensemble. Proc. Natl. Acad. Sci. USA
104: 17247-17248
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Pitteloud, N., Zhang, C., Pignatelli, D., Li, J.-D., Raivio, T., Cole, L. W., Plummer, L., Jacobson-Dickman, E. E., Mellon, P. L., Zhou, Q.-Y., Crowley, W. F. Jr.
(2007). From the Cover: Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc. Natl. Acad. Sci. USA
104: 17447-17452
[Abstract][Full Text]
Dhillo, W. S., Chaudhri, O. B., Thompson, E. L., Murphy, K. G., Patterson, M., Ramachandran, R., Nijher, G. K., Amber, V., Kokkinos, A., Donaldson, M., Ghatei, M. A., Bloom, S. R.
(2007). Kisspeptin-54 Stimulates Gonadotropin Release Most Potently during the Preovulatory Phase of the Menstrual Cycle in Women. J. Clin. Endocrinol. Metab.
92: 3958-3966
[Abstract][Full Text]
Lapatto, R., Pallais, J. C., Zhang, D., Chan, Y.-M., Mahan, A., Cerrato, F., Le, W. W., Hoffman, G. E., Seminara, S. B.
(2007). Kiss1 / Mice Exhibit More Variable Hypogonadism than Gpr54 / Mice. Endocrinology
148: 4927-4936
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Luque, R. M., Kineman, R. D., Tena-Sempere, M.
(2007). Regulation of Hypothalamic Expression of KiSS-1 and GPR54 Genes by Metabolic Factors: Analyses Using Mouse Models and a Cell Line. Endocrinology
148: 4601-4611
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Li, D., Mitchell, D., Luo, J., Yi, Z., Cho, S.-G., Guo, J., Li, X., Ning, G., Wu, X., Liu, M.
(2007). Estrogen Regulates KiSS1 Gene Expression through Estrogen Receptor {alpha} and SP Protein Complexes. Endocrinology
148: 4821-4828
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Wilson, M. A., Meaux, S., van Hoof, A.
(2007). A Genomic Screen in Yeast Reveals Novel Aspects of Nonstop mRNA Metabolism. Genetics
177: 773-784
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Marot, D., Bieche, I., Aumas, C., Esselin, S., Bouquet, C., Vacher, S., Lazennec, G., Perricaudet, M., Kuttenn, F., Lidereau, R., de Roux, N.
(2007). High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors. Endocr Relat Cancer
14: 691-702
[Abstract][Full Text]
Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F. Jr., Pitteloud, N.
(2007). Reversal of Idiopathic Hypogonadotropic Hypogonadism. NEJM
357: 863-873
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Kauffman, A. S., Park, J. H., McPhie-Lalmansingh, A. A., Gottsch, M. L., Bodo, C., Hohmann, J. G., Pavlova, M. N., Rohde, A. D., Clifton, D. K., Steiner, R. A., Rissman, E. F.
(2007). The Kisspeptin Receptor GPR54 Is Required for Sexual Differentiation of the Brain and Behavior. J. Neurosci.
27: 8826-8835
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Luan, X., Zhou, Y., Wang, W., Yu, H., Li, P., Gan, X., Wei, D., Xiao, J.
(2007). Association study of the polymorphisms in the KISS1 gene with central precocious puberty in Chinese girls. Eur J Endocrinol
157: 113-118
[Abstract][Full Text]
Rometo, A. M., Krajewski, S. J., Lou Voytko, M., Rance, N. E.
(2007). Hypertrophy and Increased Kisspeptin Gene Expression in the Hypothalamic Infundibular Nucleus of Postmenopausal Women and Ovariectomized Monkeys. J. Clin. Endocrinol. Metab.
92: 2744-2750
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