Introduction: Mutations of the human GNRH1 gene are an extremely rare cause of normosmic idiopathic hypogonadotropic hypogonadism (nIHH), with only 6 mutations so far described. Patients: As part of a larger study, families with IHH were screened for mutations in genes known to be associated with IHH. In family 1, a 15-year and 9-month-old boy first presented during infancy with micropenis and bilateral cryptorchidism. His pubic and axillary hair is at stage 4 and 2, respectively. His testes are 1 ml bilaterally, and his stretched penile length is 3.6 cm. In family 2, a 19-year and 2-month-old man was referred because of absence of secondary sexual characteristics. His 13-year and 8-month-old sister did not have any breast development. Results: In 3 patients from 2 independent families we identified GNRH1 mutations. In the proband from family 1, a homozygous 1-base deletion (c.87delA) leading to a frameshift mutation (p.G29GfsX12) was identified. In family 2, the affected siblings had a novel homozygous mutation of c.G92A leading to p.R31H. Conclusion: Both mutations in these families are located in the region encoding the decapeptide and in the loci where the mutations have been described before. Therefore, these areas can be considered as mutational hot spots, indicating priority for routine diagnostic gene mutation analysis.

Keywords:
Idiopathic hypogonadotropic hypogonadism, Puberty, GNRH1
1.
Plant TM: Hypothalamic control of the pituitary-gonadal axis in higher primates: key advances over the last two decades. J Neuroendocrinol 2008;20:719-726.
2.
Topaloglu AK, Kotan LD: Molecular causes of hypogonadotropic hypogonadism. Curr Opin Obstet Gynecol 2010;22:264-270.
3.
Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F, Tsiaras S, Gaspert A, Lavoie HB, Wu CH, Crowley WF Jr, et al: GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci USA 2009;106:11703-11708.
4.
Chan YM: A needle in a haystack: mutations in GNRH1 as a rare cause of isolated GnRH deficiency. Mol Cell Endocrinol 2011;346:51-56.
5.
Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombes M, Millar RP, Guiochon-Mantel A, Young J: Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med 2009;360:2742-2748.
6.
Bouligand J, Ghervan C, Trabado S, Brailly-Tabard S, Guiochon-Mantel A, Young J: Genetics defects in GNRH1: a paradigm of hypothalamic congenital gonadotropin deficiency. Brain Res 2010;1364:3-9.
7.
Maione L, Albarel F, Bouchard P, Gallant M, Flanagan CA, Bobe R, Cohen-Tannoudji J, Pivonello R, Colao A, Brue T, et al: R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism. PLoS One 2013;8:e69616.
8.
Lehman MN, Coolen LM, Goodman RL: Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010;151:3479-3489.
9.
de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E: Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003;100:10972-10976.
10.
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, et al: The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349:1614-1627.
11.
Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, et al: TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet 2009;41:354-358.
12.
Palmert MR, Dunkel L: Clinical practice. Delayed puberty. N Engl J Med 2012;366:443-453.
13.
Kaplowitz PB: Delayed puberty. Pediatr Rev 2010;3:189-195.
14.
Beranova M, Oliveira LM, Bedecarrats GY, Schipani E, Vallejo M, Ammini AC, Quintos JB, Hall JE, Martin KA, Hayes FJ, et al: Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2001;86:1580-1588.
15.
Bédécarrats GY, Kaiser UB: Mutations in the human gonadotropin-releasing hormone receptor: insights into receptor biology and function. Semin Reprod Med 2007;25:368-378.
16.
Gurbuz F, Kotan LD, Mengen E, Siklar Z, Berberoglu M, Dokmetas S, Kilicli MF, Guven A, Kirel B, Saka N, et al: Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism. J Clin Res Pediatr Endocrinol 2012;4:121-126.
17.
Tuncbilek E, Koc I: Consanguineous marriage in Turkey and its impact on fertility and mortality. Ann Hum Genet 1994;58:321-329.
18.
Donbak L: Consanguinity in Kahramanmaras city, Turkey, and its medical impact. Saudi Med J 2004;25:1991-1994.
19.
Cattanach BM, Iddon CA, Charlton HM, Chiappa SA, Fink G: Gonadotrophin-releasing hormone deficiency in a mutant mouse with hypogonadism. Nature 1977;269:338-340.
20.
Grumbach MM: Mutations in the synthesis and action of estrogen: the critical role in the male of estrogen on pubertal growth, skeletal maturation, and bone mass. Ann NY Acad Sci 2004;1038:7-13.
21.
Quaynor SD, Kim HG, Cappello EM, Williams T, Chorich LP, Bick DP, Sherins RJ, Layman LC: The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril 2011;96:1424-1430.e1426.
22.
Millar RP: GnRHs and GnRH receptors. Anim Reprod Sci 2005;88:5-28.
23.
Cheng CK, Leung PC: Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev 2005;26:283-306.
24.
Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR: Gonadotropin-releasing hormone receptors. Endocr Rev 2004;25:235-275.
25.
Sealfon SC, Weinstein H, Millar RP: Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr Rev 1997;18:180-205.
26.
Millar RP, Flanagan CA, Milton RC, King JA: Chimeric analogues of vertebrate gonadotropin-releasing hormones comprising substitutions of the variant amino acids in positions 5, 7, and 8. Characterization of requirements for receptor binding and gonadotropin release in mammalian and avian pituitary gonadotropes. J Biol Chem 1989;264:21007-21013.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.