A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N- nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation

Andrew J. Pask, Haruhiko Kanasaki, Ursula B. Kaiser, P. Michael Conn, Jo Ann Janovick, David W. Stockton, David Hess, Monica J. Justice, Richard R. Behringer

    Research output: Contribution to journalArticle

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    Abstract

    An autosomal-recessive mutation that causes hypogonadotrophic hypogonadism was isolated during an N-ethyl-N-nitrosourea mutagenesis screen in mice. Affected males had micropenis and small, undescended testes with spermatogenesis arrested at the pschytene stage of meiosis, leading to sterility. Androgen-sensitive organs were small and immature. Affected females were externally normal but sterile with small ovaries due to an arrest at the secondary stage of folliculogenesis, and the uterus and oviducts were thin and immature. Circulating reproductive hormones were significantly decreased in affected males and females. There was also a dramatic reduction in the numbers of FSH- and LH-producing gonadotrophs. Meiotic mapping of the mutation and candidate gene sequencing determined that the N-ethyl-N-nitrosourea-induced lesion is in the third transmembrane domain of the GnRH receptor gene (Gnrhr). In vitro studies indicate that the mutant receptor is not coupled to the plasma membrane signal transduction system. Moreover, this mutant cannot be rescued with defined GnRH receptor pharmacoperones (pharmacological chaperones), an approach that rescues many other misfolded mutants. The mutant GnRH receptor was also shown to exert a dominant-negative effect on wild-type receptor function, indicating that the mutant receptor is unable to fold properly and likely misrouted within the cell, not reaching the plasma membrane. Surprisingly, Gnrhr mutant transcripts were significantly up-regulated in the pituitaries of Gnrhr mutants, revealing a previously unknown autoregulatory feedback loop. This is the first report of a mouse with a Gnrhr loss of function mutation. These GnRH-insensitive mice provide a novel animal model for the study of human idiopathic hypogonadotrophic hypogonadism.

    Original languageEnglish (US)
    Pages (from-to)972-981
    Number of pages10
    JournalMolecular Endocrinology
    Volume19
    Issue number4
    DOIs
    StatePublished - Apr 2005

    Fingerprint

    Ethylnitrosourea
    LHRH Receptors
    Hypogonadism
    Mutation
    Genes
    Cell Membrane
    Gonadotrophs
    Cryptorchidism
    Oviducts
    Meiosis
    Spermatogenesis
    Gonadotropin-Releasing Hormone
    Mutagenesis
    Infertility
    Androgens
    Uterus
    Ovary
    Signal Transduction
    Animal Models
    Hormones

    ASJC Scopus subject areas

    • Molecular Biology
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Pask, A. J., Kanasaki, H., Kaiser, U. B., Conn, P. M., Janovick, J. A., Stockton, D. W., ... Behringer, R. R. (2005). A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N- nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. Molecular Endocrinology, 19(4), 972-981. https://doi.org/10.1210/me.2004-0192

    A novel mouse model of hypogonadotrophic hypogonadism : N-ethyl-N- nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. / Pask, Andrew J.; Kanasaki, Haruhiko; Kaiser, Ursula B.; Conn, P. Michael; Janovick, Jo Ann; Stockton, David W.; Hess, David; Justice, Monica J.; Behringer, Richard R.

    In: Molecular Endocrinology, Vol. 19, No. 4, 04.2005, p. 972-981.

    Research output: Contribution to journalArticle

    Pask, AJ, Kanasaki, H, Kaiser, UB, Conn, PM, Janovick, JA, Stockton, DW, Hess, D, Justice, MJ & Behringer, RR 2005, 'A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N- nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation', Molecular Endocrinology, vol. 19, no. 4, pp. 972-981. https://doi.org/10.1210/me.2004-0192
    Pask, Andrew J. ; Kanasaki, Haruhiko ; Kaiser, Ursula B. ; Conn, P. Michael ; Janovick, Jo Ann ; Stockton, David W. ; Hess, David ; Justice, Monica J. ; Behringer, Richard R. / A novel mouse model of hypogonadotrophic hypogonadism : N-ethyl-N- nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation. In: Molecular Endocrinology. 2005 ; Vol. 19, No. 4. pp. 972-981.
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