Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure
Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure
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DOI：
10.1093/hmg/ddn274
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Dahl, Niklas
中科院分区：
文献类型：
--
作者：
Mansouri, Mahmoud Reza;Schuster, Jens;Dahl, Niklas
卵巢早衰（POF）是以40岁以前的高促性腺激素性性腺功能减退和闭经为特征。这种情况具有异质性背景，但家族性病例的发生证明了遗传因素。我们发现了一对患有POF的母女，她们都携带X染色体常染色体易位[t（X;11）（q24;q13）]。X染色体断裂点侧翼基因的RNA表达研究显示，两名患者的基因Progesterone Receptor Membrane Component-1（PGRMC 1）表达水平降低。对67例特发性POF女性患者进行突变筛查，发现第三例患者的错义突变（H165 R）位于PGRMC 1的细胞色素b5结构域。PGRMC 1介导卵巢细胞中孕酮的抗凋亡作用，并作为几种细胞色素P450（CYP）催化反应的正调节剂。CYP对细胞内固醇代谢，包括类固醇激素的生物合成至关重要。我们发现，与POF相关的H165 R突变废除了细胞色素P450 7A 1（CYP 7A 1）与PGRMC 1的结合。此外，错义突变减弱了PGRMC 1介导卵巢细胞中孕酮抗凋亡作用的能力。这些发现表明PGMRC 1的突变或水平降低可能通过微粒体细胞色素P450的活化受损和卵巢细胞凋亡增加引起POF。
Premature ovarian failure (POF) is characterized by hypergonadotropic hypogonadism and amenorrhea before the age of 40. The condition has a heterogeneous background but genetic factors are demonstrated by the occurrence of familial cases. We identified a mother and daughter with POF both of whom carry an X;autosome translocation [t(X;11)(q24;q13)]. RNA expression studies of genes flanking the X-chromosome breakpoint revealed that both patients have reduced expression levels of the gene Progesterone Receptor Membrane Component-1 (PGRMC1). Mutation screening of 67 females with idiopathic POF identified a third patient with a missense mutation (H165R) located in the cytochrome b5 domain of PGRMC1. PGRMC1 mediates the anti-apoptotic action of progesterone in ovarian cells and it acts as a positive regulator of several cytochrome P450 (CYP)-catalyzed reactions. The CYPs are critical for intracellular sterol metabolism, including biosynthesis of steroid hormones. We show that the H165R mutation associated with POF abolishes the binding of cytochrome P450 7A1 (CYP7A1) to PGRMC1. In addition, the missense mutation attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells. These findings suggest that mutant or reduced levels of PGMRC1 may cause POF through impaired activation of the microsomal cytochrome P450 and increased apoptosis of ovarian cells.