Morphogenetic targets and genetics of undescended testis

Sexual Development

Volumn 4, Issue 6, 2010, Pages 326-335

  Massart, F ^a,b   Saggese, G ^a  

^a UNIVERSITY OF PISA   (Italy)

^b Department of Pediatrics   (Italy)

Author keywords

Cryptorchidism; Gene; Gubernaculum; Homeobox; INSL3; LGR8; Mutation; Polymorphism; Zinc finger

Indexed keywords

G PROTEIN COUPLED RECEPTOR; INSULIN; LEYDIG INSULIN LIKE PROTEIN; LEYDIG INSULIN-LIKE PROTEIN; PROTEIN; ZINC FINGER PROTEIN;

CRYPTORCHISM; GENETICS; HOMEOBOX; HUMAN; MALE; MORPHOGENESIS; REVIEW;

CRYPTORCHIDISM; GENES, HOMEOBOX; HUMANS; INSULIN; MALE; MORPHOGENESIS; PROTEINS; RECEPTORS, G-PROTEIN-COUPLED; ZINC FINGERS;

EID: 78049325881     PISSN: 16615425     EISSN: 16615433     Source Type: Journal    
DOI: 10.1159/000321006     Document Type: Review

References (101)

1. Adham IM, Agoulnik AI: Insulin-like 3 signalling in testicular descent. Int J Androl 27: 257-265 (2004).
2. Adham IM, Burkhardt E, Benahmed M, Engel W: Cloning of a cDNA for a novel insulinlike peptide of the testicular Leydig cells. J Biol Chem 268: 26668-26672 (1993).
3. Adham IM, Steding G, Thamm T, Bullesbach EE, Schwabe C, Paprotta I, Engel W: The overexpression of the Insl3 in female mice causes descent of the ovaries. Mol Endocri-nol 16: 244-252 (2002).
4. Agoulnik AI: Cryptorchidism-an estrogen spoil? J Clin Endocrinol Metab 90: 4975-4977 (2005).
5. Alders M, Ryan A, Hodges M, Bliek J, Feinberg AP, et al: Disruption of a novel imprinted zinc-finger gene, ZNF215 , in Beckwith-Wie-demann Syndrome. Am J Hum Genet 66: 1473-1484 (2000).
6. Baker LA, Nef S, Nguyen MT, Stapleton R, Nor-denskjold A, Pohl H, Parada LF: The insu-lin-3 gene: lack of a genetic basis for human cryptorchidism. J Urol 167: 2534-2537 (2002).
7. Bartone FF, Schmidt MA: Cryptorchidism: incidence of chromosomal anomalies in 50 cases. J Urol 127: 1105-1106 (1982).
8. Bathgate RA, Ivell R, Sanborn BM, Sherwood OD, Summers RJ: International Union of Pharmacology LVII: recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev 58: 7-31 (2006).
9. Benacerraf BR, Bromley B: Sonographic finding of undescended testes in fetuses at 35-40 weeks: significance and outcome. J Clin Ultrasound 26: 69-71 (1998).
10. Benson GV, Nguyen TH, Maas RL: The expression pattern of the murine Hoxa-10 gene and the sequence recognition of its homeodo-main reveal specific properties of Abdominal B-like genes. Mol Cell Biol 15: 1591-1601 (19 95
11. Bertini V, Bertelloni S, Va let to A, Lala R, Forest a C, Simi P: Homeobox HOXA10 gene analysis in cryptorchidism. J Pediatr Endocrinol Metab 17: 41-45 (2004).
12. Bili?ska B, Wiszniewska B, Kosiniak-Kamysz K, Kotula-Balak M, Gancarczyk M, et al: Hormonal status of male reproductive system: androgens and estrogens in the testis and ep-ididymis. In vivo and in vitro approaches. Reprod Biol 6: 43-58 (2006).
13. Bogatcheva NV, Truong A, Feng S, Engel W, Ad-ham IM, Agoulnik AI: GREAT/LGR8 is the only receptor for insulin-like 3 peptide. Mol Endocrinol 17: 2639-2646 (2003).
14. Bogatcheva NV, Ferlin A, Feng S, Truong A, Gianesello L, Foresta C, Agoulnik AI: 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 292:E138-E144 (2007).
15. Boisen KA, Kaleva M, Main KM, Virtanen HE, Haavisto AM, et al: Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet 363: 1264-1269 (2004).
16. Botas J: Control of morphogenesis and differentiation by Hom/HOX genes. Curr Opin Cell Biol 5: 1015-1022 (1993).
17. Braun T, Schofield PR, Sprengel R: Amino-ter-minal leucine-rich repeats in gonadotropin receptors determine hormone selectivity. EMBO J 10: 1885-1890 (1991).
18. Bullesbach EE, Schwabe C: The primary structure and the disulfide links of the bovine re-laxin-like factor (RLF). Biochemistry 41: 274-281 (2002).
19. Burkhardt E, Adham IM, Brosig B, Gastmann A, Mattei MG, Engel W: Structural organization of the porcine and human genes coding for a Leydig cell-specific insulin-like peptide (LEY I-L) and chromosomal localization of the human gene (INSL3). Genomics 20: 13-9 (1994).
20. Canto P, Escudero I, Soderlund D, Nishimura E, Carranza-Lira S, et al: A novel mutation of t he insulin-l i ke 3 gene in pat ients w ith cr y pt-orchidism. J Hum Genet 48: 86-90 (2003).
21. Carragher AM, McLean RD: Familial bilateral cry ptorchid ism. Br J Clin Pract 44: 688-689 (199 0
22. Chan JJ, Farmer PJ, Southwell BR, Sourial M, Hutson JM: Calcitonin gene-related peptide is a survival factor, inhibiting apoptosis in neonatal rat gubernaculum in vitro. J Pediatr Surg 44: 1497-1501 (2009).
23. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM: Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 10: 1527-1535 (1996).
24. Czeizel A, Erodi E, Toth J: Genetics of unde-scended testis. J Urol 126: 528-529 (1981).
25. Dadze S, Wieland C, Jakubiczka S, Funke K, Schroder E, et al: The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Cau-casoid sample of German origin. Mol Hum Reprod 6: 207-214 (2000).
26. Dewald GW, Kelalis PP, Gordon H: Chromosomal studies in cryptorchidism. J Urol 117: 110-112 (1977).
27. Dowsing AT, Yong EL, Clark M, McLachlan RI, de Kretser DM, Trouson A: Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet 354: 6 4 0-6 4 3 (199 9
28. Duboule D, Dollé P: The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeo-tic genes. EMBO J 8: 1497-1505 (1989).
29. Elert A, Jahn K, Heidenreich A, Hofmann R: The familial undescended testis. Klin Padiatr 215: 40-45 (2003).
30. El Houate B, Rouba H, Sibai H, Barakat A, Chafik A, et al: Novel mutations involving the INSL3 gene associated with cryptorchi-dism. J Urol 177: 1947-1951 (2007).
31. Feng S, Cortessis VK, Hwang A, Hardy B, Koh CJ, Bogatcheva N V, Agoulnik AI: Mutation a n a lysis of INSL3 and GR E AT/LGR 8 gene s i n familial cryptorchidism. Urology 64: 1032-1036 (2004).
32. Ferl i n A, Si monato M, Ba r toloni L , R izz o G, Bet-tella A, et al: The INSL3-LGR8/GREAT li-gand-receptor pair in human cryptorchi-dism. J Clin Endocrinol Metab 88 4273-4279 (2003).
33. Ferlin A, Bogatcheva NV, Gianesello L, Pepe A, Vinanzi C, Agoulnik AI, Foresta C: Insulinlike factor 3 gene mutations in testicular dys-genesis syndrome: clinical and functional characterization. Mol Hum Reprod 12: 401-406 (2006).
34. Ferlin A, Zuccarello D, Garolla A, Selice R, Vi-nanzi C, et al: Mutations in INSL3 and RXFP2 genes in cryptorchid boys. Ann N YAcad Sci 1160: 213-214 (2009).
35. Foresta C, Ferlin A: Role of INSL3 and LGR8 in cr y ptorchid ism and testicu lar f unct ions. Re-prod Biomed Online 9: 294-298 (2004).
36. Foresta C, Ferlin A, Garolla A, Milani C, Oliva G, Rossato M: Functional and cytologic features of the contralateral testis in cryptorchi-dism. Fertil Steril 66: 624-629 (1996).
37. Foresta C, Zuccarello D, Garolla A, Ferlin A: Role of hormones, genes, and environment in human cryptorchidism. Endocr Rev 29: 560-580 (2008).
38. Gianotten J, van der Veen F, Alders M, Leschot NJ, Tanck MW, et al: Chromosomal region 11p15 is associated with male factor subfer-tility. Mol Hum Reprod 9: 587-592 (2003).
39. Giwercman A, von der Maase H, Skakkebaek NE: Epidemiological and clinical aspects of carcinoma in situ of the testis. Eur Urol 23: 104-110 (1993).
40. Gorlov IP, Kamat A, Bogatcheva N V, Jones E, Lamb DJ, et al: Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet 11: 2309-2318 (2002).
41. Grantham R: Amino acid difference formula to help explain protein evolution. Science 185: 862-864 (1974).
42. Halls ML, Bond CP, Sudo S, Kumagai J, Ferraro T, et al: 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 313: 677-687 (2005).
43. Hong S, Phang T, Ji I, Ji TH: The amino-terminal region of the luteinizing hormone/choriogo-nadotropin receptor contacts both subunits of human choriogonadotropin. I. Mutational ana lysis. J Biol Chem 273: 13835-13840 (19 98
44. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ: Activation of orphan receptors by the hormone re-laxin. Science 295: 671-674 (2002).
45. Hutson JM, Hasthorpe S, Heyns CF: Anatomical and functional aspects of testicular descent and cryptorchidism. Endocr Rev 18: 259-280 (19 97
46. Ivell R: Biology of the relaxin-like factor (RLF). Rev Reprod 2: 133-138 (1997).
47. Ivell R, Hartung S: The molecular basis of crypt-orchidism. Mol Hum Reprod 9: 175-181 (2003).
48. Kaefer M, Diamond D, Hendren WH, Vemula-palli S, Bauer SB, et al: The incidence of in-tersexuality in children w it h cr yptorchidism and hypospadias: stratification based on go-nadal palpability and meatal position. J Urol 16 2 : 1003-1006 (1999).
49. Kogan S: Cryptorchidism, in Kelalis PP, King LR and Belman AB (eds): Clinical Pediatric Urology, vol. 2, pp. 1050-1083 (W. B. Saun-ders Co., Philadelphia 1992
50. Kolon TF, Wiener JS, Lewitton M, Roth DR, Gonzales ET Jr, Lamb DJ: Analysis of ho-meobox gene HOXA10 mutations in cryptor-chidism. J Urol 161: 275-280 (1999).
51. Koskimies P, Virtanen H, Lindstrom M, Kaleva M, Poutanen M, Huhtaniemi I, Toppari J: A common polymorphism in the human relax-in-like factor (RLF) gene: no relationship w ith cr yptorchidism. Pediatr Res 47: 538-541 (2000).
52. Koskimies P, Levallet J, Sipilä P, Huhtaniemi I, Pout a nen M: Mu rine rela xin-like factor pro-moter: functional characterization and regulation by transcription factors steroidogen-ic factor 1 and DAX-1. Endocrinology 143: 909-919 (2002).
53. Krausz C, Quintana-Murci L, Fellous M, Siffroi JP, McElreavey K: Absence of mutations involving the INSL3 gene in human idiopathic cryptorchidism. Mol Hum Reprod 6: 298-302 (2000).
54. Kruglyak L: Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22: 139-144 (1999).
55. Layman LC: Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am 36: 283-296 (2007).
56. Lee JE, Choi JH, Lee JH, Lee MG: Gene SNPs and mutations in clinical genetic testing: haplo-type-based testing and analysis. Mutat Res 573: 195-204 (2005).
57. Lim HN, Chen H, McBride S, Dunning AM, Nixon RM, Hughes IA, Hawkins JR: Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males. Hum Mol Genet 9: 829-834 (2000).
58. Lim HN, Raipert-de Meyts E, Skakkebaek NE, Hawkins JR, Hughes IA: Genetic analysis of the INSL3 gene in patients with maldescent of the testis. Eur J Endocrinol 144: 129-137 (2001).
59. Marin P, Ferlin A, Moro E, Rossi A, Bartoloni L, Rossato M, Foresta C: Novel insulin-like 3 (INSL3) gene mutation associated with human cryptorchidism. Am J Med Genet 103: 348-349 (2001a
60. Marin P, Ferlin A, Moro E, Garolla A, Foresta C: Different insulin-like 3 (INSL3) gene mutations not associated with human cryptorchi-dism. J Endocrinol Invest 24:RC13-RC15 (2001b
61. Massart F, Saggese G: Sex steroidal targets and genetic susceptibility to idiopathic cryptor-chidism. Pediatr Endocrinol Rev 6: 481-490 (2009).
62. Massart F, Reginster JY, Brandi ML: Genetics of menopause-associated diseases. Maturitas 40: 103-116 (2001).
63. McAleer IM, Kaplan GW: Is routine karyotyping necessary in the evaluation of hypospadias and cryptorchidism. J Urol 165: 2029-2031 (2001).
64. McGinnis W, K r umlauf R: Homeobox genes and axial patterning. Cell 68: 283-302 (1992).
65. Moreno-Garcia M, Miranda EB: Chromosomal anomalies in cryptorchidism and hypospa-dias. J Urol 168: 2170-2172 (2002).
66. Moutou C, Junien C, Henry I, Bonaiti-Pellie C: Beckwith-Wiedemann syndrome: a demonstration of the mechanisms responsible for the excess of transmitting females. J Med Genet 29: 217-220 (1992).
67. Muroya K, Sasagawa I, Suzuk i Y, Na kada T, Ishii T, Ogata T: Hypospadias and the androgen receptor gene: mutation screening and CAG repeat length analysis. Mol Hum Reprod 7: 409-413 (2001).
68. Nagayama Y, Wadsworth HL, Chazenbalk GD, Russo D, Seto P, Rapoport B: Thyrotropin-luteinizing hormone/chorionic gonadotro-pin receptor extracellular domain chimeras as probes for thyrotropin receptor function. Proc Natl Acad Sci USA 88: 902-905 (1991).
69. Nef S, Parada LF: Cryptorchidism in mice mu-ta nt for Insl3. Nat Genet 22: 295-299 (1999).
70. Nightingale SS, Western P, Hutson JM: The migrating gubernaculum grows like a 'limb bud '. J Pediatr Surg 43: 387-390 (2008).
71. Nowotny T, Bollmann R, Pfeifer L, Windt E: Beckwith-Wiedemann syndrome: difficulties with prenatal diagnosis. Fetal Diagn Ther 9: 256-260 (1994).
72. Nuti F, Marinari E, Erdei E, El-Hamshari M, Echavarria MG, et al: The leucine-rich repeat-containing G protein-coupled receptor 8 gene T222P mutation does not cause crypt-orchidism. J Clin Endocrinol Metab 93: 1072-1076 (2008).
73. Osuga Y, Kudo M, Kaipia A, Kobilka B, Hsueh AJ: Derivation of functional antagonists using N-terminal extracellular domain of go-nadotropin and thyrotropin receptors. Mol Endocrinol 11: 1659-1668 (1997).
74. Overbeek PA, Gorlov IP, Sutherland RW, Houston JB, Harrison WR, et al: A transgenic insertion causing cryptorchidism in mice. Genesis 30: 26-35 (2001).
75. Pa rdo-Mi nda n FJ, Va r ga s Torca l F, Ga rcia Ju l i a n G, Virto Ruiz MT: Letter: Familial cryptor-chidism. Pediatrics 56: 616 (1975).
76. Pernice F, Mazza G, Puglisi D, Luppino MG, Fri-sina N: Nonrobertsonian translocation t(6; 11) is associated with infertility in an oligo-zoospermic male. Fertil Steril 78: 192-194 (2002).
77. Perrett LJ, O'Rourke DA: Hereditary cryptorchi-dism. Med J Aust 1: 1289-1290 (1969).
78. Pettenati MJ, Haines JL, Higgins RR, Wappner RS, Palmer CG, Weaver DD: Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet 74: 143-154 (1986).
79. Rijli FM, Matyas R, Pellegrini M, Dierich A, Gruss P, Dollé P, Chambon P: Cryptorchi-dism and homeotic transformations of spinal ner ves and vertebrae in Hoxa-10 mutant mice. Proc Natl Acad Sci USA 92: 818 5-818 9 (19 9 5
80. Roh J, Virtanen H, Kumagai J, Sudo S, Kaleva M, Toppari J, Hsueh AJ: Lack of LGR8 gene mutation in Finnish patients with a family history of cryptorchidism. Reprod Biomed Online 7: 400-406 (2003).
81. Rohatgi M, Menon PSN, Verma IC, Iyengar JK: The presence of intersexuality in patients with advanced hypospadias and undescend-ed gonads. J Urol 137: 263-267 (1987).
82. Sasagawa I, Nakada T, Ishigooka M, Sawamura T, Adachi Y, Hashimoto T: Chromosomal anomalies in cryptorchidism. Int Urol Nephrol 28: 99-102 (1996).
83. Satokata I, Benson G, Maas R: Sexually dimorphic sterility phenotypes in Hoxa-10-defi-cient mice. Nature 374: 460-463 (1995).
84. Savion M, Nissenkorn I, Servadio C, Dickerman Z: Familial occurrence of undescended tes-tes. Urology 23: 355-358 (1984).
85. Sharpe RM, Skakkebaek NE: Testicular dysgen-esis syndrome: mechanistic insights and potential new downstream effects. Fertil Steril 89:e33-e38 (2008).
86. Simoni M, Tüttelmann F, Michel C, Böckenfeld Y, Nieschlag E, Gromoll J: Polymorphisms of the luteinizing hormone/chorionic gonado-tropin receptor gene: association with mal-descended testes and male infertility. Phar-macogenet Genomics 18: 193-200 (2008).
87. Sudo S, Kumagai J, Nishi S, Layfield S, Ferraro T, Bathgate RA, Hsueh AJ: H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2. J Biol Chem 278: 7855-7862 (2003).
88. Takahashi I, Takahashi T, Komatsu M, Matsuda J, Takada G: Ala/Thr60 variant of the Leydig insulin-like hormone is not associated with cryptorchidism in the Japanese population. Pediatr Int 43: 256-258 (2001).
89. Tashima LS, Hieber AD, Greenwood FC, Bryant-Greenwood GD: The human Leydig insulin-like (hLEY I-L) gene is expressed in the corpus luteum and trophoblast. J Clin Endo-crinol Metab 80: 707-710 (1995).
90. Tomboc M, Lee PA, Mitwally MF, Schneck FX, Bellinger M, Witchel SF: Insulin-like 3/re-laxin-like factor gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab 85: 4013-4018 (2000).
91. van der Zanden LF, van Rooij IA, Feitz WF, Ver-meulen SH, Kiemeney LA, et al: Genetics of hypospadias: are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 really associated with the malformation? J Clin Endocrinol Metab 95: 2384-2390 (2010).
92. Versiani BR, Trarbach E, Koenigkam-Santos M, Dos Santos AC, Elias LL, et al: Clinical assessment and molecular analysis of GnRHR and KAL1 genes in males with idiopathic hy-pogonadotrophic hypogonadism. Clin Endocrinol 66: 173-179 (2007).
93. Vischer HF, Granneman JC, Bogerd J: Opposite contribution of two ligand-selective determinants in the N-terminal hormone-binding exodomain of human gonadotropin receptors. Mol Endocrinol 17: 1972-1981 (2003a
94. Vischer HF, Granneman JC, Noordam MJ, Mos-selman S, Bogerd J: Ligand selectivity of gonadotropin receptors. Role of the fS-strands of extracellular leucine-rich repeats 3 and 6 of the human luteinizing hormone receptor. J Biol Chem 278: 15505-15513 (2003b
95. Warr N, Siggers P, Bogani D, Brixey R, Pastorel-li L, et al: Sfrp1 and Sfrp2 are required for normal male sexual development in mice. Dev Biol 326: 273-284 (2009).
96. -/- male mice. J Androl 30: 452-459 (2009).
97. Yamaguchi T, Kitada S, Osada Y: Chromosomal anomalies in cryptorchidism and hypospadias. Urol Int 47: 60-63 (1991).
98. Yamazawa K, Wada Y, Sasagawa I, Aoki K, Ueo-ka K, Ogata T: Mutation and polymorphism analyses of INSL3 and LGR8/GREAT in 62 Japanese patients with cryptorchidism. Horm Res 67: 73-76 (2007).
99. Yun YJ, Lee HC, Kim JE, Song SH, Lee S: Preliminary analysis of the G178A polymorphism of insulin-like factor 3 in male infertility. Fertil Steril 88: 1706-1708 (2007).
100. Zimmermann S, Schöttler P, Engel W, Adham IM: Mouse Leydig insulin-like (Ley I-L) gene: structure and expression during testis and ovary development. Mol Reprod Dev 47: 30-38 (1997).
101. Zimmermann S, Steding G, Emmen JM, Brink-mann AO, Nayernia K, et al: Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 13: 681-691 (1999).