Mice harboring GNRHR E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure

M. David Stewart, Jian Ming Deng, C. Allison Stewart, Rachael D. Mullen, Ying Wang, Suhujey Lopez, M. Katalina Serna, Cheng Chiu Huang, Jo Ann Janovick, Andrew J. Pask, Robert J. Schwartz, P. Michael Conn, Richard R. Behringer

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

GnRH, produced in the hypothalamus, acts on pituitary gonadotropes to stimulate release of the gonadotropins LH and FSH. Reduced responsiveness of gonadotropes to GnRH is a primary cause of hypogonadotropic hypogonadism (HH), a disease characterized by gonadal dysfunction and low blood levels of gonadotropins. Loss-of-function mutations in the gene encoding the receptor for GnRH (GNRHR) are a common cause of HH. Sequencing of the GNRHR gene in patients with HH revealed mainly point mutations producing single amino acid substitutions that cause misfolding and misrouting of this G protein-coupled receptor. To generate a mouse model that mimics the human disease, we introduced a single amino acid substitution (E90K) into the mouse Gnrhr gene, which is identical to a known human recessive mutation. In humans, E90K causes severe HH by preventing formation of the E90-K121 salt bridge, which is essential for correct folding. In cell cultures, E90K causes misfolding that leads to almost complete retention by the protein quality control system and subsequent degradation. Here we report that the primary phenotype of mice homozygous for E90K is female infertility due to ovulation failure. Mutant males are fertile despite reduced gonadotropin levels and smaller testes. These results suggest decreased GnRH receptor signaling in the mutant animal, compared with wild type. Our findings suggest that a threshold level of GnRH receptor activity is required for ovulation.

Original languageEnglish (US)
Pages (from-to)1847-1856
Number of pages10
JournalMolecular Endocrinology
Volume26
Issue number11
DOIs
StatePublished - Nov 5 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    David Stewart, M., Deng, J. M., Allison Stewart, C., Mullen, R. D., Wang, Y., Lopez, S., Katalina Serna, M., Huang, C. C., Janovick, J. A., Pask, A. J., Schwartz, R. J., Michael Conn, P., & Behringer, R. R. (2012). Mice harboring GNRHR E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure. Molecular Endocrinology, 26(11), 1847-1856. https://doi.org/10.1210/me.2012-1072