Human Molecular Genetics

This Article Full Text FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (85) Request Permissions Google Scholar Articles by Gorlov, I. P. Articles by Agoulnik, A. I. Search for Related Content PubMed PubMed Citation Articles by Gorlov, I. P. Articles by Agoulnik, A. I. Social Bookmarking          What's this?

Human Molecular Genetics, 2002, Vol. 11, No. 19 2309-2318
© 2002 Oxford University Press

Mutations of the GREAT gene cause cryptorchidism

Ivan P. Gorlov¹, Aparna Kamat¹, Natalia V. Bogatcheva¹, Eric Jones², Dolores J. Lamb^2,3, Anne Truong¹, Colin E. Bishop^1,4, Ken McElreavey⁵ and Alexander I. Agoulnik^1,*

¹Department of Obstetrics and Gynecology, ²Scott Department of Urology, ³Department of Molecular and Cellular Biology and ⁴Human and Molecular Genetics Department, Baylor College of Medicine, Houston, TX 77030, USA and ⁵Reproduction, Fertility and Populations, Institut Pasteur, 75724, Paris Cedex 15, France

Received May 20, 2002; Accepted July 17, 2002

In humans, failure of testicular descent (cryptorchidism) is one of the most frequent congenital malformations, affecting 1–3% of newborn boys. The clinical consequences of this abnormality are infertility in adulthood and a significantly increased risk of testicular malignancy. Recently, we described a mouse transgene insertional mutation, crsp, causing high intraabdominal cryptorchidism in homozygous males. A candidate gene Great (G-protein-coupled receptor affecting testis descent), was identified within the transgene integration site. Great encodes a seven-transmembrane receptor with a close similarity to the glycoprotein hormone receptors. The Great gene is highly expressed in the gubernaculum, the ligament that controls testicular movement during development, and therefore may be responsible for mediating hormonal signals that affect testicular descent. Here we show that genetic targeting of the Great gene in mice causes infertile bilateral intraabdominal cryptorchidism. The mutant gubernaculae fail to differentiate, indicating that the Great gene controls their development. Mutation screening of the human GREAT gene was performed using DHPLC analysis of the genomic DNA from 60 cryptorchid patients. Nucleotide variations in GREAT cDNA were found in both the patient and the control populations. A unique missense mutation (T222P) in the ectodomain of the GREAT receptor was identified in one of the patients. This mutant receptor fails to respond to ligand stimulation, implicating the GREAT gene in the etiology in some cases of cryptorchidism in humans.

^* To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Baylor College of Medicine, 6550 Fannin Street, Suite 861, Houston, TX 77030, USA. Tel: +1 7137986087; Fax: +1 7137985074; Email: agoulnik{at}bcm.tmc.edu

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				C. Foresta, D. Zuccarello, A. Garolla, and A. Ferlin Role of Hormones, Genes, and Environment in Human Cryptorchidism Endocr. Rev., August 1, 2008; 29(5): 560 - 580. [Abstract] [Full Text] [PDF]

				E. E Bullesbach, F. R Boockfor, G. Fullbright, and C. Schwabe Cryptorchidism induced in normal rats by the relaxin-like factor inhibitor Reproduction, March 1, 2008; 135(3): 351 - 355. [Abstract] [Full Text] [PDF]

				F. Nuti, E. Marinari, E. Erdei, M. El-Hamshari, M. G. Echavarria, E. Ars, G. Balercia, M. Merksz, C. Giachini, K. Z. M. Shaeer, et al. The Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 8 Gene T222P Mutation Does Not Cause Cryptorchidism J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 1072 - 1076. [Abstract] [Full Text] [PDF]

				H.E. Virtanen and J. Toppari Epidemiology and pathogenesis of cryptorchidism Hum. Reprod. Update, January 1, 2008; 14(1): 49 - 58. [Abstract] [Full Text] [PDF]

				C. R. Cederroth, O. Schaad, P. Descombes, P. Chambon, J.-D. Vassalli, and S. Nef Estrogen Receptor {alpha} Is a Major Contributor to Estrogen-Mediated Fetal Testis Dysgenesis and Cryptorchidism Endocrinology, November 1, 2007; 148(11): 5507 - 5519. [Abstract] [Full Text] [PDF]

				K. Bay, H. E. Virtanen, S. Hartung, R. Ivell, K. M. Main, N. E. Skakkebaek, A.-M. Andersson, The Nordic Cryptorchidism Study Group, and J. Toppari Insulin-Like Factor 3 Levels in Cord Blood and Serum from Children: Effects of Age, Postnatal Hypothalamic-Pituitary-Gonadal Axis Activation, and Cryptorchidism J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 4020 - 4027. [Abstract] [Full Text] [PDF]

				S. Feng, N. V Bogatcheva, A. Truong, B. Korchin, C. E Bishop, T. Klonisch, I. U Agoulnik, and A. I Agoulnik Developmental Expression and Gene Regulation of Insulin-like 3 Receptor RXFP2 in Mouse Male Reproductive Organs Biol Reprod, October 1, 2007; 77(4): 671 - 680. [Abstract] [Full Text] [PDF]

				A. Kern, A. I. Agoulnik, and G. D. Bryant-Greenwood The Low-Density Lipoprotein Class A Module of the Relaxin Receptor (Leucine-Rich Repeat Containing G-Protein Coupled Receptor 7): Its Role in Signaling and Trafficking to the Cell Membrane Endocrinology, March 1, 2007; 148(3): 1181 - 1194. [Abstract] [Full Text] [PDF]

				N. V. Bogatcheva, A. Ferlin, S. Feng, A. Truong, L. Gianesello, C. Foresta, and A. I. Agoulnik T222P mutation of the insulin-like 3 hormone receptor LGR8 is associated with testicular maldescent and hinders receptor expression on the cell surface membrane Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E138 - E144. [Abstract] [Full Text] [PDF]

				A. Ferlin, N.V. Bogatcheva, L. Gianesello, A. Pepe, C. Vinanzi, A.I. Agoulnik, and C. Foresta Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization Mol. Hum. Reprod., June 1, 2006; 12(6): 401 - 406. [Abstract] [Full Text] [PDF]

				M. P. Del Borgo, R. A. Hughes, R. A. D. Bathgate, F. Lin, K. Kawamura, and J. D. Wade Analogs of Insulin-like Peptide 3 (INSL3) B-chain Are LGR8 Antagonists in Vitro and in Vivo J. Biol. Chem., May 12, 2006; 281(19): 13068 - 13074. [Abstract] [Full Text] [PDF]

				R. J.K. Anand-Ivell, V. Relan, M. Balvers, I. Coiffec-Dorval, M. Fritsch, R. A.D. Bathgate, and R. Ivell Expression of the Insulin-Like Peptide 3 (INSL3) Hormone-Receptor (LGR8) System in the Testis Biol Reprod, May 1, 2006; 74(5): 945 - 953. [Abstract] [Full Text] [PDF]

				R. A. Bathgate, R. Ivell, B. M. Sanborn, O. D. Sherwood, and R. J. Summers International Union of Pharmacology LVII: Recommendations for the Nomenclature of Receptors for Relaxin Family Peptides. Pharmacol. Rev., March 1, 2006; 58(1): 7 - 31. [Abstract] [Full Text] [PDF]

				C. Staub, M. Rauch, F. Ferriere, M. Trepos, I. Dorval-Coiffec, P. T. Saunders, G. Cobellis, G. Flouriot, C. Saligaut, and B. Jegou Expression of Estrogen Receptor ESR1 and Its 46-kDa Variant in the Gubernaculum Testis Biol Reprod, October 1, 2005; 73(4): 703 - 712. [Abstract] [Full Text] [PDF]

				M. Muda, C. He, P. G.V. Martini, T. Ferraro, S. Layfield, D. Taylor, C. Chevrier, R. Schweickhardt, C. Kelton, P. L. Ryan, et al. Splice variants of the relaxin and INSL3 receptors reveal unanticipated molecular complexity Mol. Hum. Reprod., August 1, 2005; 11(8): 591 - 600. [Abstract] [Full Text] [PDF]

				K. Bay, S. Hartung, R. Ivell, M. Schumacher, D. Jurgensen, N. Jorgensen, M. Holm, N. E. Skakkebaek, and A.-M. Andersson Insulin-Like Factor 3 Serum Levels in 135 Normal Men and 85 Men with Testicular Disorders: Relationship to the Luteinizing Hormone-Testosterone Axis J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3410 - 3418. [Abstract] [Full Text] [PDF]

				M. L. Halls, C. P. Bond, S. Sudo, J. Kumagai, T. Ferraro, S. Layfield, R. A. D. Bathgate, and R. J. Summers Multiple Binding Sites Revealed by Interaction of Relaxin Family Peptides with Native and Chimeric Relaxin Family Peptide Receptors 1 and 2 (LGR7 and LGR8) J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 677 - 687. [Abstract] [Full Text] [PDF]

				E. E. Bullesbach and C. Schwabe LGR8 Signal Activation by the Relaxin-like Factor J. Biol. Chem., April 15, 2005; 280(15): 14586 - 14590. [Abstract] [Full Text] [PDF]

				A. Ferlin, A. Garolla, A. Bettella, L. Bartoloni, C. Vinanzi, A. Roverato, and C. Foresta Androgen receptor gene CAG and GGC repeat lengths in cryptorchidism Eur. J. Endocrinol., March 1, 2005; 152(3): 419 - 425. [Abstract] [Full Text] [PDF]

				J. Chen, C. Kuei, S. W. Sutton, P. Bonaventure, D. Nepomuceno, E. Eriste, R. Sillard, T. W. Lovenberg, and C. Liu Pharmacological Characterization of Relaxin-3/INSL7 Receptors GPCR135 and GPCR142 from Different Mammalian Species J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 83 - 95. [Abstract] [Full Text] [PDF]

				C. Foresta, A. Bettella, C. Vinanzi, P. Dabrilli, M. C. Meriggiola, A. Garolla, and A. Ferlin A Novel Circulating Hormone of Testis Origin in Humans J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5952 - 5958. [Abstract] [Full Text] [PDF]

				G. Vinci, M.-N. Anjot, C. Trivin, H. Lottmann, R. Brauner, and K. McElreavey An Analysis of the Genetic Factors Involved in Testicular Descent in a Cohort of 14 Male Patients with Anorchia J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6282 - 6285. [Abstract] [Full Text] [PDF]

				E. L. Aschim, A. Nordenskjold, A. Giwercman, K. B. Lundin, Y. Ruhayel, T. B. Haugen, T. Grotmol, and Y. L. Giwercman Linkage between Cryptorchidism, Hypospadias, and GGN Repeat Length in the Androgen Receptor Gene J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5105 - 5109. [Abstract] [Full Text] [PDF]

				A. A. Kamat, S. Feng, N. V. Bogatcheva, A. Truong, C. E. Bishop, and A. I. Agoulnik Genetic Targeting of Relaxin and Insulin-Like Factor 3 Receptors in Mice Endocrinology, October 1, 2004; 145(10): 4712 - 4720. [Abstract] [Full Text] [PDF]

				K. Kawamura, J. Kumagai, S. Sudo, S.-Y. Chun, M. Pisarska, H. Morita, J. Toppari, P. Fu, J. D. Wade, R. A. D. Bathgate, et al. Paracrine regulation of mammalian oocyte maturation and male germ cell survival PNAS, May 11, 2004; 101(19): 7323 - 7328. [Abstract] [Full Text] [PDF]

				N. V. Bogatcheva, A. Truong, S. Feng, W. Engel, I. M. Adham, and A. I. Agoulnik GREAT/LGR8 Is the Only Receptor for Insulin-Like 3 Peptide Mol. Endocrinol., December 1, 2003; 17(12): 2639 - 2646. [Abstract] [Full Text] [PDF]

				A. Truong, N. V. Bogatcheva, C. Schelling, G. Dolf, and A. I. Agoulnik Isolation and Expression Analysis of the Canine Insulin-Like Factor 3 Gene Biol Reprod, November 1, 2003; 69(5): 1658 - 1664. [Abstract] [Full Text] [PDF]

				A. Ferlin, M. Simonato, L. Bartoloni, G. Rizzo, A. Bettella, T. Dottorini, B. Dallapiccola, and C. Foresta The INSL3-LGR8/GREAT Ligand-Receptor Pair in Human Cryptorchidism J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4273 - 4279. [Abstract] [Full Text] [PDF]

				R. Ivell and S. Hartung The molecular basis of cryptorchidism Mol. Hum. Reprod., April 1, 2003; 9(4): 175 - 181. [Abstract] [Full Text] [PDF]

Online ISSN 1460-2083 - Print ISSN 0964-6906

Copyright © 2009 Oxford University Press

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics