的分子基础hypogonadotropic性腺机能减退:恢复突变体激性腺素释放素受体(E (90) K)函数在一个遥远的网站删除。
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Maya-Nunez G, Janovick JA, Ulloa-Aguirre索德伦德D,康涅狄格州点,门德斯JP
的分子基础hypogonadotropic性腺机能减退:恢复突变体激性腺素释放素受体(E (90) K)函数在一个遥远的网站删除。
87年5月,中国性金属底座。2002 (5):2144 - 9。
- PubMed ID
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11994356 (在PubMed]
- 文摘
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促性腺激素调节垂体促性腺激素的合成和释放。激性腺素释放素受体(hGnRHR)基因突变在人类已报告在家庭hypogonadotropic性腺机能减退。我们小组最近描述了一个新颖的纯合子E (90) K hGnRHR突变的两个兄弟姐妹的完整形式hypogonadotropic性腺机能减退。在目前的研究中,突变分析E (90) K替换进行评估这个残留的功能作用,位于第二hGnRHR的跨膜螺旋。尽管E(90)是高度保守的在所有其他已知的哺乳动物促性腺激素受体,这残以前没有涉及促绑定和/或GnRHR激活。瞬时表达突变的E (90) K COS-7细胞受体导致虚拟废除促性腺绑定和agonist-stimulated磷酸肌醇营业额,最初表明E(90)可能是必不可少的促绑定。此外,孵化1 microM不同的促性腺激素受体激动剂(D-Trp(6)促促,leuprolide, Catfish-1促,Catfish-2促,D-Lys(6)专业(9)-EA-GnRH DesGly(10)促,D-Trp(6)专业(9)-EA-GnRH Buserelin,和D-Lys(6)促)或拮抗剂(Antide和“Nal-Arg”)并没有导致高架肌醇磷酸生产从细胞表达E (90) K突变。检查网站的作用被抑制hGnRHR函数,突变体与删除K (191) (DeltaK(191)从hGnRHR和/或添加鲶鱼GnRHR胞内羧基末端尾巴(cfCtail) hGnRHR准备。暴露在促模拟Buserelin导致显著增加细胞表达hGnRHR-cfCtail总磷酸肌醇生产hGnRHR (DeltaK(191))和hGnRHR (DeltaK (191)) -cfCtail。激活细胞内信号以响应Buserelin恢复删除的K (191) E (90) K受体突变体,但除了最小的鲶鱼GnRHR羧基末端尾巴。 There were no significant differences in total inositol phosphate production between the chimeric receptors bearing the DeltaK(191) or the E(90)K/DeltaK(191) modifications. All but the (E(90)K) and (E(90)K)-cfCtail altered receptors were membrane expressed as disclosed by Western blot analysis of epitope-tagged receptors. This study provides evidence that the E(90)K mutation impairs hGnRHR-effector coupling. The observation that sequence modifications that enhance surface expression of the receptor restore function, presents the possibility that loss of surface expression may underlie the severe phenotype exhibited by hypogonadotropic hypogonadism patients bearing this mutational defect.