Female mice expressing constitutively active mutants of FSH receptor present with a phenotype of premature follicle depletion and estrogen excess.
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 mFshr(D580H) 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 mFshr(D580H) 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 mFSHR(D580Y) mutation is milder, mainly causing hemorrhagic cysts in transgenic mFSHR(D580Y) and mFSHR(D580Y) -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.
Peltoketo
Hellevi
H
Institute of Reproductive and Developmental Biology, 2nd floor, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.
Strauss
Leena
L
Karjalainen
Riikka
R
Zhang
Meilin
M
Stamp
Gordon W
GW
Segaloff
Deborah L
DL
Poutanen
Matti
M
Huhtaniemi
Ilpo T
IT
D000311:Adrenal Glands / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation; D004967:Estrogens / Q000096:biosynthesis / Q000097:blood*; D030762:Estrous Cycle / Q000235:genetics; D005260:Female; D007246:Infertility / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008321:Mammary Glands, Animal / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009929:Organ Size; D006080:Ovarian Follicle / Q000473:pathology*; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010902:Pituitary Gland / Q000473:pathology; D011374:Progesterone / Q000096:biosynthesis; D011388:Prolactin / Q000097:blood; D011962:Receptors, FSH / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D004967:Estrogens; D011962:Receptors, FSH; D011374:Progesterone; D011388:Prolactin