Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene

Nature Genetics volume 9, pages 160–164 (1995)Cite this article

Abstract

Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. We have studied two Leydig cell hypoplasia patients (siblings born to consanguineous parents), and found them to be homozygous for a missense mutation (Ala593Pro) in the sixth transmembrane domain of the luteinizing hormone (LH) receptor gene. In vitro expression studies showed that this mutated receptor binds human choriogonadotropin with a normal KD, but the ligand binding does not result in increased production of cAMP. We conclude that a homozygous LH receptor gene mutation underlies the syndrome of autosomal recessive congenital Leydig cell hypoplasia in this family. These results have implications for the understanding of the development of the male genitalia.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Jost, A. Hormonal factors in the sex differentiation of the mammalian foetus. Philos. Trans. R. Soc. Lond. Biol. 259, 119–130 (1970).

    Article  CAS  Google Scholar 

  2. Nordqvist, K. & Lovell-Badge, R. Setbacks on the road to sexual fulfilment. Nature Genet. 7, 7–9 (1994).

    Article  CAS  Google Scholar 

  3. Huhtaniemi, I. Fetal testis—a very special endocrine organ. Eur. J. Endocrinol. 130, 25–31 (1994).

    Article  CAS  Google Scholar 

  4. Patsavoudi, E., Magre, S., Castanier, M., Scholler, R. & Jost, A. Dissociation between testicular morphogenesis and functional differentiation of Leydig cells. J. Endocrinol. 105, 235–238 (1985).

    Article  CAS  Google Scholar 

  5. Schwartz, M. et al. Male pseudohermaphroditism secondary to an abnormality in Leydig cell differentiation. J. clin. endocrinol. Metab. 53, 123–127 (1981).

    Article  CAS  Google Scholar 

  6. Martinez-Mora, J. et al. Male pseudohermaphroditism due to Leydig cell agenesia and absence of testicular LH receptors. Clin. Endocrinol. 34, 485–491 (1991).

    Article  CAS  Google Scholar 

  7. Perez-Palacios, G. et al. Inherited male pseudohermaphroditism due to gonadotrophin unresponsiveness. Acta. Endocrinol. 98, 148–55 (1981).

    Article  CAS  Google Scholar 

  8. Lee, P.A. et al. Leydig cell hypofunction resulting in male pseudohermaphroditism. Fertil. Steril. 37, 675–679 (1982).

    Article  CAS  Google Scholar 

  9. Toledo, S.P.A., Amhold, I.J., Luthold, W., Russo, E.M. & Saldanha, P.H. Leydig cell hypoplasia determining familial hypergonadotropic hypogonadism. Prog. Clin. Biol. Res. 200, 311–314 (1985).

    CAS  PubMed  Google Scholar 

  10. Toledo, S.P.A. Leydig cell hypoplasia leading to two different phenotypes: male pseudohermaphroditism and primary hypogonadism not associated with this Clin. Endocrinol. 36, 521–522 (1992).

    Article  CAS  Google Scholar 

  11. EI-Awady, M.K., Temtamy, S.A., Salam, M.A. & Gad, Y.Z., Familial Leydig cell hypoplasia as a cause of male pseudohermaphroditism. Hum. Hered. 37, 36–40 (1987).

    Article  Google Scholar 

  12. Saldanha, P.H., Amhold, I.J., Mendonca, B.B., Bloise, W. & Toledo, S.P.A. A cllnico-genetlc investigation of Leydig cell hypoplasia.Am J. med. Genet. 26, 337–344 (1987).

    Article  CAS  Google Scholar 

  13. Arnhold, I.J. et al. Leydig cell hypoplasia causing male pseudohermaphroditism: case report and review of the literature. Rev Hosp. Clin. Fac. Med. Sao Paulo. 42, 227–232 (1987).

    CAS  PubMed  Google Scholar 

  14. Warren, D.W., Huhtaniemi, I.T., Tapanainen, J., Dufau, M.L. & Catt, K.J. Ontogeny of gonadotropln receptors in the fetal and neonatal rat testis. Endocrinology. 114, 470–476 (1984).

    Article  CAS  Google Scholar 

  15. Braun, T., Schofield, P.R. & Sprengel, R. Amino-terminal leucine-rich repeats in gonadotropin receptors determine hormone selectivity. EMBO J. 10, 1885–1890 (1991).

    Article  CAS  Google Scholar 

  16. Shenker, A. et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature. 365, 652–654 (1993).

    Article  CAS  Google Scholar 

  17. Kremer, H. et al. Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. Hum. molec. Genet. 2, 1779–1783 (1993).

    Article  CAS  Google Scholar 

  18. Clements, J.A., Reyes, F.I., Winter, J.S. & Faiman, C. Studies on human sexual development. III. Fetal pituitary and serum, and amniotic fluid concentrations of LH, CG, and FSH. J. clin. endocrinol. Metab. 42, 9–19 (1976).

    Article  CAS  Google Scholar 

  19. Huhtaniemi, I.T., Korenbrot, C.C. & Jaffe, R.B. HCG binding and stimulation of testosterone biosynthesis in the human fetal testis.J clln endocrinol. Metab. 44, 963–967 (1977).

    Article  CAS  Google Scholar 

  20. Huhtaniemi, I. & Pelliniemi, L.J. Fetal Leydig cells: cellular origin, morphology, life span, and special functional features. Proc. Soc. Exp. Biol. Med. 201, 125–140 (1992).

    Article  CAS  Google Scholar 

  21. Zhang, F.P., Hamalainen, T., Kaipia, A., Pakarinen, P. & Huhtaniemi, I. Ontogeny of luteinizing hormone receptor gene expression in the rat testis. Endocrinology. 134, 2206–2213 (1994).

    Article  CAS  Google Scholar 

  22. Molenaar, R., de Rooij, D.G., Rommerts, F.F.G. & van der Molen, H.J. Repopulation of Leydig cells in mature rats after selective destruction of the existent Leydig cells with ethylene dimethane sulfonate is dependent on luteinizing hormone and not follicle-stimulating hormone. Endocrinology 118, 2546–2554 (1986).

    Article  CAS  Google Scholar 

  23. Kuopio, T., Pelliniemi, L.J. & Huhtaniemi, I., Rapid Leydig cell proliferation and luteinizing hormone receptor replenishment in the neonatal rat testis after a single injection of human chorionlc gonadotropin. Biol. Reprod. 40, 135–143 (1989).

    Article  CAS  Google Scholar 

  24. Murono, E.P., Washbum, A.L. & Goforth, D.P. Enhanced stimulation of 5 alpha-reductase activity in cultured Leydig cell precursors by human chononic gonadotropin. J. Steroid Biochem. molec. Biol. 48, 377–384 (1994).

    Article  CAS  Google Scholar 

  25. George, F.W., Catt, K.J., Neaves, W.B. & Wilson, J.D. Studies on the regulation of testosterone synthesis in the fetal rabbit testis. Endocrinology 102, 665–673 (1978).

    Article  CAS  Google Scholar 

  26. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucl. Adds Res. 16, 1215 (1988).

    Article  CAS  Google Scholar 

  27. Minegishi, T. et al. Cloning and sequencing of human LH/hCG receptor cDNA. Biochem. Biophys. Res. Comm. 172, 1049–1054 (1990).

    Article  CAS  Google Scholar 

  28. Green, S., Issemann, I. & Sheer, E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucl. Acids Res. 16, 369 (1988).

    Article  CAS  Google Scholar 

  29. Higuchl, R., Krummel, B. & Saiki, R.K. A general method of in vitro preparation and specific mutagenesis of DNA fragments: study of protein and DNA interactions.Nucl. Acids Res. 16, 7351–7367 (1988).

    Article  Google Scholar 

  30. Chen, C. & Okayama, H. High-efficiency transformation of mammalian cells by plasmid DNA. Molec. Cell. Biol. 7, 2745–2752 (1987).

    Article  CAS  Google Scholar 

  31. Ketelslegers, J.M. & Catt, K.J. Follitropin receptors in rat testis. Characterization with enzymatically 125l-labeled human follitropin. Biochlm. Biophys. Acta. 541, 360–371 (1978).

    Article  CAS  Google Scholar 

  32. van Dijk, M.A., van Schalk, F.M., Bootsma, H.J., Holthuizen, P. & Sussenbach, J.S. Initial characterization of the four promoters of the human insulin-like growth factor II gene. Molec. Cell. Endocrinol. 81, 81–94 (1991).

    Article  CAS  Google Scholar 

  33. Themmen, A.P.N. et al. Follitropin receptor down-regulation involves a cAMP-dependent post-transcriptional decrease of receptor mRNA expression. Mol. Cell. Endocrinol. 78, R7–13 (1991).

    Article  CAS  Google Scholar 

  34. Stoof, J.C., Vertieijden, P.F. & Leysen, J.E. Stimulation of D2-receptors in rat nucleus accumbens slices inhibits dopamine and acetylcholine release but not cyclic AMP formation. Brain Res. 423, 364–368 (1987).

    Article  CAS  Google Scholar 

  35. Blok, L.J. et al. Transcriptional regulation of androgen receptor gene expression in Sertoli cells and other cell types. Molec. Cell Endocrinol. 88, 153–64 (1992).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Genetics, University Hospital, Nijmegen, The Netherlands

    Hannie Kremer, Margo van Reen, Hans-Hilger Ropers, Edwin Mariman & Han G. Brunner

  2. Department of Endocrinology & Reproduction, Erasmus University Rotterdam, Rotterdam, The Netherlands

    Robert Kraaij, Miriam Post & Axel P.N. Themmen

  3. Endocrine Genetics Unit, Endocrine Division, Department of Medicine, Sao Paulo University School of Medicine, Sao Paulo, Brazil

    Sergio P.A. Toledo, Julia B. Fridman & Cesar Y. Hayashida

  4. Unité de Récherche Hormones et Réproduction, INSERM U135, Faculté de Médecine de Bicêtre, Université de Paris, Paris, France

    Edwin Milgrom

Authors
  1. Hannie Kremer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Kraaij
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sergio P.A. Toledo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miriam Post
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julia B. Fridman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cesar Y. Hayashida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Margo van Reen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Edwin Milgrom
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hans-Hilger Ropers
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Edwin Mariman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Axel P.N. Themmen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Han G. Brunner
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kremer, H., Kraaij, R., Toledo, S. et al. Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. Nat Genet 9, 160–164 (1995). https://doi.org/10.1038/ng0295-160

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0295-160

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing