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Submitted on May 6, 2004
Accepted on December 20, 2004
Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Department of Zoology, University of Melbourne, Victoria 3010, Australia; Division of Endocrinology, Diabetes, and Hypertension, Harvard Medical School, Boston, Massachusetts 02115; Departments of Physiology and Pharmacology, and Cell and Developmental Biology, Oregon Health & Science University, Oregon 97006; Oregon National Primate Research Center, Divisions of Neuroscience, Reproductive Sciences and Research Services, Beaverton, Oregon 97006; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030
* To whom correspondence should be addressed. E-mail: rrb{at}mdanderson.org.
An autosomal recessive mutation that causes hypogonadotrophic hypogonadism was isolated during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice. Affected males had micropenis and small, undescended testes with spermatogenesis arrested at the pachytene 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 2o 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 (FSH) and LH (LH) producing gonadotrophs. Meiotic mapping of the mutation and candidate gene sequencing determined that the ENU-induced lesion is in the third transmembrane domain of the gonadotrophin-releasing hormone (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.
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