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Gene Review

INSL3  -  insulin-like 3 (Leydig cell)

Homo sapiens

Synonyms: Insulin-like 3, Ley-I-L, Leydig insulin-like peptide, MGC119818, MGC119819, ...
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Disease relevance of INSL3

  • The frequency of INSL3/RLF gene mutations as a cause of cryptorchidism is low, because only 2 of 145 (1.4%) formerly cryptorchid patients were found to have mutations [1].
  • Subjects with severe testicular damage, such as men with severe infertility, produce low amount of INSL3, and the concentrations of this hormone seem to reflect the functional status of the Leydig cells [2].
  • In the present study we have investigated the expression of human INSL3 in patients with benign prostate hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and prostate carcinoma tissues [3].
  • We screened for mutations in INSL3 gene in 967 subjects with a history of maldescended testes and/or infertility and/or testicular cancer and in 450 controls [4].
  • By contrast, thyrocytes of all 15 benign goiter tissues studied were devoid of both INSL-3 isoforms, mRNA and protein [5].

High impact information on INSL3

  • The relaxin-like factor (RLF, also named INSL3) is a critical component in the chain of events that lead to the normal positioning of the gonads in the male fetus [6].
  • In as much as these major binding residues seem hardly sufficient to explain the strong binding of RLF to LGR8 we searched for and found an extended region where little contributions by individual residues added up to a strong receptor affinity [6].
  • Insulin-like peptide 3 (INSL3), a member of the relaxin peptide family, is produced in testicular Leydig cells and ovarian thecal cells [7].
  • Additionally, INSL3 has an important function in mediating male and female germ cell function [7].
  • Alanine-substituted analogs were used to identify the key residues of INSL3 that are responsible for the interaction with the ectodomain of LGR8 [7].

Chemical compound and disease context of INSL3


Biological context of INSL3


Anatomical context of INSL3


Associations of INSL3 with chemical compounds

  • In particular, INSL3 concentrations may be an even more sensitive marker of Leydig cell function than testosterone itself [2].
  • All-trans-retinoic acid was demonstrated in PC-3 to up-regulate LGR8 gene activity in a dose- and time-dependent manner while having no effect on INSL3 gene activity [3].
  • To identify the structural features that are responsible for the interaction of INSL3 with its receptor, its solution structure was determined by NMR spectroscopy together with in vitro assays of a series of B-chain alanine-substituted analogs [7].
  • Northern blot analysis indicated that the LGR8 transcripts are expressed in gubernaculum whereas treatment of cultured gubernacular cells with INSL3 stimulated cAMP production and thymidine incorporation [13].
  • We also synthesized analogues of INSL3, with amino acid substitutions in the arginine-binding region [14].

Other interactions of INSL3


Analytical, diagnostic and therapeutic context of INSL3


  1. Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism. Tomboc, M., Lee, P.A., Mitwally, M.F., Schneck, F.X., Bellinger, M., Witchel, S.F. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  2. A novel circulating hormone of testis origin in humans. Foresta, C., Bettella, A., Vinanzi, C., Dabrilli, P., Meriggiola, M.C., Garolla, A., Ferlin, A. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  3. INSL3 in the benign hyperplastic and neoplastic human prostate gland. Klonisch, T., Müller-Huesmann, H., Riedel, M., Kehlen, A., Bialek, J., Radestock, Y., Holzhausen, H.J., Steger, K., Ludwig, M., Weidner, W., Hoang-Vu, C., Hombach-Klonisch, S. Int. J. Oncol. (2005) [Pubmed]
  4. Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Ferlin, A., Bogatcheva, N.V., Gianesello, L., Pepe, A., Vinanzi, C., Agoulnik, A.I., Foresta, C. Mol. Hum. Reprod. (2006) [Pubmed]
  5. INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes. Hombach-Klonisch, S., Hoang-Vu, C., Kehlen, A., Hinze, R., Holzhausen, H.J., Weber, E., Fischer, B., Dralle, H., Klonisch, T. Int. J. Oncol. (2003) [Pubmed]
  6. The mode of interaction of the relaxin-like factor (RLF) with the leucine-rich repeat G protein-activated receptor 8. Büllesbach, E.E., Schwabe, C. J. Biol. Chem. (2006) [Pubmed]
  7. Solution Structure and Characterization of the LGR8 Receptor Binding Surface of Insulin-like Peptide 3. Rosengren, K.J., Zhang, S., Lin, F., Daly, N.L., Scott, D.J., Hughes, R.A., Bathgate, R.A., Craik, D.J., Wade, J.D. J. Biol. Chem. (2006) [Pubmed]
  8. Serum Insulin-Like Factor 3 Levels during Puberty in Healthy Boys and Boys with Klinefelter Syndrome. Wikstr??m, A.M., Bay, K., Hero, M., Andersson, A.M., Dunkel, L. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  9. Reproductive biology of the relaxin-like factor (RLF/INSL3). Ivell, R., Bathgate, R.A. Biol. Reprod. (2002) [Pubmed]
  10. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. Foster, P.M. Int. J. Androl. (2006) [Pubmed]
  11. T222P mutation of the insulin-like 3 hormone receptor LGR8 is associated with testicular maldescent and hinders receptor expression on the cell surface membrane. Bogatcheva, N.V., Ferlin, A., Feng, S., Truong, A., Gianesello, L., Foresta, C., Agoulnik, A.I. Am. J. Physiol. Endocrinol. Metab. (2007) [Pubmed]
  12. The molecular basis of cryptorchidism. Ivell, R., Hartung, S. Mol. Hum. Reprod. (2003) [Pubmed]
  13. INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. Kumagai, J., Hsu, S.Y., Matsumi, H., Roh, J.S., Fu, P., Wade, J.D., Bathgate, R.A., Hsueh, A.J. J. Biol. Chem. (2002) [Pubmed]
  14. Structural requirements for the interaction of sheep insulin-like factor 3 with relaxin receptors in rat atria. Tan, Y.Y., Dawson, N.F., Kompa, A.R., Bond, C.P., Claasz, A., Wade, J.D., Tregear, G.W., Summers, R.J. Eur. J. Pharmacol. (2002) [Pubmed]
  15. Relaxin research in the postgenomic era. Kawamura, K., Sudo, S., Kumagai, J., Pisarska, M., Hsu, S.Y., Bathgate, R., Wade, J., Hsueh, A.J. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  16. Human medullary thyroid carcinoma: a source and potential target for relaxin-like hormones. Klonisch, T., Mustafa, T., Bialek, J., Radestock, Y., Holzhausen, H.J., Dralle, H., Hoang-Vu, C., Hombach-Klonisch, S. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  17. Mutation analysis of INSL3 and GREAT/LGR8 genes in familial cryptorchidism. Feng, S., Cortessis, V.K., Hwang, A., Hardy, B., Koh, C.J., Bogatcheva, N.V., Agoulnik, A.I. Urology (2004) [Pubmed]
  18. The human Leydig insulin-like (hLEY I-L) gene is expressed in the corpus luteum and trophoblast. Tashima, L.S., Hieber, A.D., Greenwood, F.C., Bryant-Greenwood, G.D. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  19. Seasonal expression of INSL3 and Lgr8/Insl3 receptor transcripts indicates variable differentiation of Leydig cells in the roe deer testis. Hombach-Klonisch, S., Schön, J., Kehlen, A., Blottner, S., Klonisch, T. Biol. Reprod. (2004) [Pubmed]
  20. Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. Bay, K., Hartung, S., Ivell, R., Schumacher, M., Jürgensen, D., Jorgensen, N., Holm, M., Skakkebaek, N.E., Andersson, A.M. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  21. INSL3 ligand-receptor system in the equine testis. Klonisch, T., Steger, K., Kehlen, A., Allen, W.R., Froehlich, C., Kauffold, J., Bergmann, M., Hombach-Klonisch, S. Biol. Reprod. (2003) [Pubmed]
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