Advertisement

Inactivating and Activating Mutations of the FSH Receptor Gene

  • Ilpo T. Huhtaniemi
Part of the Contemporary Endocrinology book series (COE, volume 6)

Abstract

It has only recently became apparent that infertility and subfertility may be hereditary conditions. Numerous mutations have been discovered in genes that participate in the regulation of reproductive functions, and those of the gonadotropin receptors (R) have received considerable attention. Since the discovery of the first luteinizing hormone receptor (LHR) mutations in 1993 (1,2), more than 15 mutations have been so far reported in this gene (see Chapter 9, and refs. 3,4). The nature of the mutation determines to what extent the phenotype of the affected individuals is altered. “Loss-of-function” mutations usually require homozygosity or compound heterozygosity for phenotypic alterations, but with “gain-of-function” mutations, heterozygotes display altered hormonal function and phenotype. The first mutations of the follicle-stimulating hormone receptor (FSHR) have just recently been discovered. The purpose of this chapter is to review briefly the structural and functional features of the FSHR, to describe the currently known FSHR mutations, their pathophysiological consequences, and to discuss some future perspectives in the study of the role of FSHR function in reproduction.

Keywords

Granulosa Cell Sertoli Cell Precocious Puberty Luteinizing Hormone Receptor Gonadotropin Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Reference

  1. 1.
    Kremer H, Mariman E, Otten BJ, Moll GW Jr, Stoelinga GB, Wit JM, Jansen M, Drop SL, Faas B, Ropers HH, Brunner HG. Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. Hum Mol Genet 1993;2:1779–1783.PubMedCrossRefGoogle Scholar
  2. 2.
    Shenker A, Laue L, Kosugi S, Merendino JJ Jr, Minegishi T, Cutler GB Jr. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993;365:652–654.PubMedCrossRefGoogle Scholar
  3. 3.
    Huhtaniemi I, Pakarinen P, Haavisto A-M, Nilsson C, Pettersson K, Tapanainen J, Aittomäki K. The polymorphism of gonadotropin action: molecular basis and clinical implications. In: Hansson V, Levy FO, Taskén K, eds. Signal Transduction in Testicular Cells. Springer, Berlin, 1996, pp. 319–341.Google Scholar
  4. 4.
    Themmen APN, Brunner HG. Luteinizing hormone receptor mutations and sex differentiation. Eur J Endocrinol 1996;134:522–540.CrossRefGoogle Scholar
  5. 5.
    Sprengel R, Braun T, Nikolics K, Segaloff DL, Seeburg PH. The testicular receptor for follicle-stimulating hormone: structure and functional expression of cloned cDNA. Mol Endocrinol 1990;4:525–530.PubMedCrossRefGoogle Scholar
  6. 6.
    Minegishi T, Nakamura K, Takakura Y, Ibuki Y, Igarashi M. Cloning and sequencing of human FSH receptor cDNA. Biochem Biophys Res Commun 1991;175:1125–1130.PubMedCrossRefGoogle Scholar
  7. 7.
    Yarney TA, Sairam MR, Khan H, Ravindranath N, Payne S, Scidah NG. Molecular cloning and expression of the ovine testicular follicle stimulating hormone receptor. Mol Cell Endocrinol 1993;93:219–226.PubMedCrossRefGoogle Scholar
  8. 8.
    Gromoll H, Dankbar B, Sharma RS, Nieschlag E. Molecular cloning of the testicular follicle stimulating hormone receptor of the nonhuman primate Macaca fascicularis and identification of multiple transcripts in the testis. Biochem Biophys Res Commun 1993;196:1066–1072.PubMedCrossRefGoogle Scholar
  9. 9.
    Segaloff DL, Ascoli M. The lutropin/choriogonadotropin receptor … 4 years later. Endocr Rev 1993;14:324–346.PubMedGoogle Scholar
  10. 10.
    Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992;13:596–611.PubMedGoogle Scholar
  11. 11.
    Braun T, Schofield PR, Sprengel R. Amino-terminal leucine rich repeats in gonadotropin receptors determine hormone selectivity. EMBO J 1991;10:1995–2090.Google Scholar
  12. 12.
    Heckert LL, Daly IJ, Griswold MD. Structural organization of the follicle-stimulating hormone receptor gene. Mol Endocrinol 1992;6:70–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Rousseau-Merck MF, Atger M, Loosfelt H, Milgrom E, Berger R. The chromosomal localization of the human follicle-stimulating hormone receptor gene (FSHR) on 2p21-2pl5 is similar to that of the luteinizing hormone receptor gene. Genomics 1993;15:222–224PubMedCrossRefGoogle Scholar
  14. 14.
    Gromoll J, Ried T, Holtgeve-Grez H, Nieschlag E, Gudermann T. Localization of the human FSH receptor to chromosome 2p21 using a genomic probe comprising exon 10. J Mol Endocrinol 1994;12:265–271PubMedCrossRefGoogle Scholar
  15. 15.
    Gromoll J, Dankbar B, Gudermann T. Characterization of the 5′ flanking regoin of the human follicle-stimulating hormone receptor gene. Mol Cell Endocrinol 1994;102:93–102.PubMedCrossRefGoogle Scholar
  16. 16.
    Huhtaniemi IT, Eskola V, Pakarinen P, Matikainen T, Sprengel R. The murine luteinizing hormone and follicle-stimulating hormone receptor genes: transcription initiation sites, putative promoter sequences and promoter activity. Mol Cell Endocrinol 1992;88:55–66.PubMedCrossRefGoogle Scholar
  17. 17.
    Linder CC, Heckert LL, Goetz TL, Griswold MD. Follicle-stimulating hormone receptor gene promoter activity. Endocrine 1994;2:957–966.Google Scholar
  18. 18.
    Heckert LL, Griswold MD. Expression of follicle-stimulating hormone receptor mRNA in rat testis and Sertoli cells. Mol Endocrinol 1991;5:670–677.PubMedCrossRefGoogle Scholar
  19. 19.
    LaPolt PS, Tilly JL, Aihara T, Nishimori K, Hsueh AJW. Gonadotropin-induced up-and down-regulation of ovarian follicle-stimulating hormone (FSH) receptor gene expression in immature rats: effects of pregnant mare’s serum gonadotropin, human chorionic gonadotropin, and recombinant FSH. Endocrinology 1992;130:1289–1295.PubMedCrossRefGoogle Scholar
  20. 20.
    Gromoll J, Gudermann T, Nieschlag E. Molecular cloning of a truncated isoform of the human follicle stimulating hormone receptor. Biochem Biophys Res Commun 1992;188:1077–1083.PubMedCrossRefGoogle Scholar
  21. 21.
    Tilly JL, Aihara T, Nishimori K, Jia X-C, Billig H, Kowalski KI, Perlas EA, Hsueh AJW. Expression of recombinant human follicle-stimulating hormone receptor: species-specific ligand binding, signal transduction, and identification of multiple ovarian messenger ribonucleic acid transcripts. Endocrinology 1992;131:799–806.PubMedCrossRefGoogle Scholar
  22. 22.
    Griswold MD. Actions of FSH on mammalian Sertoli cells. In: Russell LD, Griswold MD, eds. The Sertoli Cell. Cache River, Clearwater, FL, 1993, pp. 493–508.Google Scholar
  23. 23.
    Camp TA, Rahal JO, Mayo KE. Cellular localization and hormonal regulation of follicle-stimulating hormone and luteinizing hormone messenger RNAs in the rat ovary. Mol Endocrinol 1991;5:1405–1417.PubMedCrossRefGoogle Scholar
  24. 24.
    Richards JS. Hormonal control of gene expression in the ovary. Endocr Rev 1994;15:725–751.PubMedGoogle Scholar
  25. 25.
    Zeleznik AJ. Dynamics of primate follicular growth. A Physiologic perspective. In: Adashi EY, Leung PCK, eds. The Ovary Raven, New York, 1993, pp. 41–55.Google Scholar
  26. 26.
    Steinkampf MP, Mendelson CR, Simpson ER. Regulation by follicle stimulating hormone of the synthesis of aromatase cytochrome P-450 in human granulosa cells. Mol Endocrinol 1987;1:465–471.PubMedCrossRefGoogle Scholar
  27. 27.
    Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnins LK, Biggers JD, Eppig JJ, Bronson RT, Elledge SJ, Weinberg RA. Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis. Nature 1996;384:470–474.PubMedCrossRefGoogle Scholar
  28. 28.
    Gondos B, Berndston WE. Postnatal and postpubertal development. In: Russell LD, Griswold MD, eds. The Sertoli Cell. Cache River, Clearwater, FL, 1993, pp. 115–194.Google Scholar
  29. 29.
    Hess RA, Cooke PS, Bunick D, Kirby JD. Adult testicular enlargement induced by neonatal hypothy-roidism is accompanied by increased Sertoli and germ cell numbers. Endocrinology 1993;132:2607–2613.PubMedCrossRefGoogle Scholar
  30. 30.
    Bremner WJ, Matsumoto AM, Sussman AM, Paulsen CA. Follicle-stimulating hormone and sper-matogenesis. J Clin Invest 1981;68:1044–1052.PubMedCrossRefGoogle Scholar
  31. 31.
    Zirkin B.R., Awoniyi C, Griswold MD, Sharpe RM. Is FSH required for adult spermatogenesis? J Androl 1994;15:273–276.PubMedGoogle Scholar
  32. 32.
    van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J, Vassart G. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab 1995;80:2577–2585.PubMedCrossRefGoogle Scholar
  33. 33.
    Utiger RD. Thyrotropin-receptor mutations and thyroid dysfunction. New Engl J Med 1995;332:183–185.PubMedCrossRefGoogle Scholar
  34. 34.
    Sunthornthepvarakul T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med 1995;332:155–160.CrossRefGoogle Scholar
  35. 35.
    Kremer H, Kraaij R, Toledo SPA, Post M, Friedman JB, Hayashida CY, van Reen M, Milgrom E, Ropers H-H, Mariman E, Themmen APN, Brunner HG. Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. Nature Gen 1995;9:160–164.CrossRefGoogle Scholar
  36. 36.
    Aittomäki K, Dieguez Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila E-M, Lehväslaiho H, Reyes Engel A, Nieschlag E, Huhtaniemi I, de la Chapelle A. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995;92:959–968.CrossRefGoogle Scholar
  37. 37.
    Gromoll J, Simoni M, Nieschlag E. An activating mutation of the follicle-stimulating hormone autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 1996;81:1367–1370.PubMedCrossRefGoogle Scholar
  38. 38.
    Aittomäki K. The genetics of XX gonadal dysgenesis. Am J Hum Genet 1994;54:844–851.PubMedGoogle Scholar
  39. 39.
    Rousseau-Merck MF, Misrahi M, Atger M, Loosfelt H, Milgrom E, Berger R. Localization of the human LH (luteinizing hormone) receptor gene to chromosome 2p21. Cytogenet Cell Genet 1990;54:77–79.PubMedCrossRefGoogle Scholar
  40. 40.
    Chelly J, Concordet J-P, Kaplan J-C, Kahn A. Illegitimate transcription: transcription of any gene in any cell type. Proc Natl Acad Sci USA 1989;86:2617–2621.PubMedCrossRefGoogle Scholar
  41. 41.
    Lei ZM, Rao ChV, Kornyei JL, Licht P, Hiatt ES. Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology 1993;132:2262–2270.PubMedCrossRefGoogle Scholar
  42. 42.
    Lin J, Lojun S, Lei ZM, Wu WX, Peiper SC, Rao ChV. Lymphocytes from pregnant women express human chorionic gonadotropin/luteinizing hormone receptor gene. Mol Cell Endocrinol 1995;111:R13–R17.PubMedCrossRefGoogle Scholar
  43. 43.
    Pabon JE, Li X, Lei ZM, Sanfilippo J, Yussman MA, Rao ChV. Novel presence of human luteinizing hormone/chorionic gonadotropin receptors in the human adrenal glands. J Clin Endocrinol Metab 1996;81:2397–2400.PubMedCrossRefGoogle Scholar
  44. 44.
    Peschon JJ, Behringer RR, Cate RL, Harwood KA, Idzerda RL, Brinster RL, Palmiter RD. Directed expression of an oncogene to Sertoli cells in transgenic mice using Mullerian inhibiting substance regulatory sequences. Mol Endocrinol 1992;6:1403–1411.PubMedCrossRefGoogle Scholar
  45. 45.
    Wahlström T, Huhtaniemi I, Hovatta O, Seppälä M. Localization of luteinizing hormone, follicle-stimulating hormone, prolactin, and their receptors in human and rat testis using immunohistochemistry and radioreceptor assay. J Clin Endocrinol Metab 1983;57:825–830.PubMedCrossRefGoogle Scholar
  46. 46.
    Aittomäki K, Herva R, Stenman U-H, Juntunen K, Ylöstalo P, Hovatta O, de la Chapelle A. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J Clin Endocrinol Metab 1996;81:3722–3726.PubMedCrossRefGoogle Scholar
  47. 47.
    Rozell TG, Wang H, Liu X, Segaloff DL. Intracellular retention of mutant gonadotropin receptors results in loss of hormone binding activity of the follitropin receptor but not the lutropin/choriogo-nadotropin receptor. Mol Endocrinol 1995;9:1727–1736.CrossRefGoogle Scholar
  48. 48.
    Davis D, Liu L, Segaloff DL. Identification of the sites of N-linked glycosylation on the follicle-stimulating hormone (FSH) receptor and assessment of their role in FSH receptor function. Mol Endocrinol 1995;9:159–170.PubMedCrossRefGoogle Scholar
  49. 49.
    Tapanainen JS, Aittomäki K, Min J, Vaskivuo T, Huhtaniemi IT. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of sper-matogenesis and infertility. Nature Genet 1997;15:205, 206.PubMedCrossRefGoogle Scholar
  50. 50.
    Maroulis GB, Parlow AF, Marshall JR. Isolated follicle-stimulating hormone deficiency in man. Fertil Steril 1977;28:818–822.PubMedGoogle Scholar
  51. 51.
    Rabinowitz D, Benveniste R, Lindner J, Lober D, Danniell J. Isolated FSH deficiency revisited. N Engl J Med 1979;300:126–128.PubMedCrossRefGoogle Scholar
  52. 52.
    Matthews CH, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G, Casagrande S, Tedeschini G, Benedetti A, Chatterjee VKK. Primary amenorrhoea and infertilitydue to a mutation in the β-subunit of follicle-stimulating hormone. Nature Genet 1993;5:83–86.PubMedCrossRefGoogle Scholar
  53. 53.
    Kumar TR, Wang Y, Lu N, Matzuk MM. Follicle stimulating hormone is required for ovarian maturation but not for male fertility. Nature Genet 1997;15:201–204.PubMedCrossRefGoogle Scholar
  54. 54.
    Singh J, O’Neill C, Handelsman DJ. Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice. Endocrinology 1995;136:5311–5321.PubMedCrossRefGoogle Scholar
  55. 55.
    Whitney EA, Layman LC, Chan PJ, Lee A, Peak DB, McDonough PG. The follicle-stimulating hormone receptor gene is polymorphic in premature ovarian failure and normal controls. Fertil Steril 1995;64:518–524.PubMedGoogle Scholar
  56. 56.
    Awoniyi CA, Zirkin BR, Chandrachekar V, Schlaff WD. Endogenously administered testosterone maintains spermatogenesis quantitatively in adult rats actively immunized against gonadotropin-releasing hormone. Endocrinology 1992;130:3283–3288.PubMedCrossRefGoogle Scholar
  57. 57.
    Weinbauer GF, Nieschlag E. Hormonal regulation of spermatogenesis. In: de Kretser D, ed. Molecular Biology of the Male Reproductive System. Academic, New York, 1993, pp. 99–142.Google Scholar
  58. 58.
    Weinbauer GF, Behre HM, Fingscheidt U, Nieschlag E. Human follicle-stimulating hormone exerts a stimulatory effect on spermatogenesis, testicular size and serum inhibin levels in the gonadotropin-releasing hormone agonist-treated, non-human primate (Macaca fascicularis). Endocrinology 1991;129:1831–1839.PubMedCrossRefGoogle Scholar
  59. 59.
    Kotlar TJ, Young RH, Albanese C, Crowley WFJr, Scully RE, Young RH, Jameson JL. A mutation in the follicle-stimulating hormone receptor occurs frequently in human ovarian sex cord tumors. J Clin Endocrinol Metab 1997;82:1020–1028.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Ilpo T. Huhtaniemi

There are no affiliations available

Personalised recommendations