内科学
内分泌学
生物
促卵泡激素受体
催乳素
受体
转基因小鼠
转基因
突变体
促性腺激素
突变
卵巢
促卵泡激素
促黄体激素
激素
基因
遗传学
医学
作者
Hellevi Peltoketo,Leena Strauss,Riikka Karjalainen,Meilin Zhang,Gordon Stamp,Deborah L. Segaloff,Matti Poutanen,Ilpo Huhtaniemi
出处
期刊:Endocrinology
[Oxford University Press]
日期:2010-02-19
卷期号:151 (4): 1872-1883
被引量:47
摘要
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.
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