Journal article
Female Mice Expressing Constitutively Active Mutants of FSH Receptor Present with a Phenotype of Premature Follicle Depletion and Estrogen Excess
Endocrinology (Philadelphia), Vol.151(4), pp.1872-1883
04/01/2010
DOI: 10.1210/en.2009-0966
PMCID: PMC2851188
PMID: 20172968
Abstract
Strong gain-of-function mutations have not been identified in humans in the FSH receptor (FSHR), whereas such mutations are common among many other G protein-coupled receptors. In order to predict consequences of such mutations on humans, we first identified constitutively activated mutants of the mouse (m) Fshr and then expressed them under the human anti-Müllerian hormone promoter in transgenic mice or created knock-in mutation into the mouse genome. We show here that mutations of Asp580 in the mFSHR significantly increase the basal receptor activity. D580H and D580Y mutations of mFSHR bind FSH, but the activity of the former is neither ligand-dependent nor promiscuous towards LH/human choriogonadotropin stimulation. Transgenic expression of mFshrD580H in granulosa cells leads to abnormal ovarian structure and function in the form of hemorrhagic cysts, accelerated loss of small follicles, augmented granulosa cell proliferation, increased estradiol biosynthesis, and occasional luteinized unruptured follicles or teratomas. The most affected mFshrD580H females are infertile with disturbed estrous cycle and decreased gonadotropin and increased prolactin levels. Increased estradiol and prolactin apparently underlie the enhanced development of the mammary glands, adenomatous pituitary growth, and lipofuscin accumulation in the adrenal gland. The influence of the mFSHRD580Y mutation is milder, mainly causing hemorrhagic cysts in transgenic mFSHRD580Y and mFSHRD580Y -knock-in mice. The results demonstrate that gain-of-function mutations of the FSHR in mice bring about distinct and clear changes in ovarian function, informative in the search of similar mutations in humans.
Details
- Title: Subtitle
- Female Mice Expressing Constitutively Active Mutants of FSH Receptor Present with a Phenotype of Premature Follicle Depletion and Estrogen Excess
- Creators
- Hellevi Peltoketo - Institute of Reproductive and Developmental Biology (H.P., R.K., I.T.H.), Imperial College London, London W12 0NN, United KingdomLeena Strauss - Department of Physiology (L.S., M.P., I.T.H.), Institute of Biomedicine, University of Turku, FIN-20520 Turku, FinlandRiikka Karjalainen - Institute of Reproductive and Developmental Biology (H.P., R.K., I.T.H.), Imperial College London, London W12 0NN, United KingdomMeilin Zhang - Department of Molecular Physiology and Biophysics (M.Z., D.L.S.), The Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242Gordon W Stamp - Department of Histopathology (G.W.S.), Hammersmith Hospital, Imperial College London, London W12 0NN, United KingdomDeborah L Segaloff - Department of Molecular Physiology and Biophysics (M.Z., D.L.S.), The Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242Matti Poutanen - Department of Physiology (L.S., M.P., I.T.H.), Institute of Biomedicine, University of Turku, FIN-20520 Turku, FinlandIlpo T Huhtaniemi - Institute of Reproductive and Developmental Biology (H.P., R.K., I.T.H.), Imperial College London, London W12 0NN, United Kingdom;, Department of Physiology (L.S., M.P., I.T.H.), Institute of Biomedicine, University of Turku, FIN-20520 Turku, Finland
- Resource Type
- Journal article
- Publication Details
- Endocrinology (Philadelphia), Vol.151(4), pp.1872-1883
- DOI
- 10.1210/en.2009-0966
- PMID
- 20172968
- PMCID
- PMC2851188
- NLM abbreviation
- Endocrinology
- ISSN
- 0013-7227
- eISSN
- 1945-7170
- Language
- English
- Date published
- 04/01/2010
- Academic Unit
- Molecular Physiology and Biophysics; Obstetrics and Gynecology
- Record Identifier
- 9984083819802771
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