Makorin环指蛋白3参与儿童中枢性性早熟的分子作用机制  

MKRN3 Regulates Central Precocious Puberty in Children

作　　者：陈子琴 张雪荣[2,3,4] CHEN Zi-Qin;ZHANG Xue-Rong(College of Chinese Medicine,Hubei University of Chinese Medicine Hubei,Wuhan 430065,China;Department of Pediatrics,Hubei Provincial Hospital of Traditional Chinese Medicine Hubei,Wuhan 430061,China;Hubei Sizhen Laboratory,Wuhan 430061,China;Department of Pediatrics,Affiliated Hospital of Hubei University of Chinese Medicine Hubei,Wuhan 430061,China)

机构地区：[1]湖北中医药大学中医学院,武汉430065 [2]湖北省中医院儿科,武汉430061 [3]湖北时珍实验室,武汉430061 [4]湖北中医药大学附属医院儿科,武汉430061

出　　处：《中国生物化学与分子生物学报》2025年第1期99-104,共6页Chinese Journal of Biochemistry and Molecular Biology

基　　金：湖北省中医药管理局面上项目(No.ZY2023M065);湖北省自然科学基金创新发展联合基金重点项目(No.2023AFD117)资助。

摘　　要：中枢性性早熟(central precocious puberty,CPP)的发病机制是由于下丘脑-垂体-性腺轴功能的提前启动,而该轴由来自下丘脑的促性腺激素释放激素(gonadotrophin-releasing hormone,GnRH)调控,GnRH分泌增加会促进垂体分泌促性腺激素,从而导致生殖器官的发育和性激素的分泌。青春期启动的时间受到营养、环境和社会经济因素之间相互作用的影响。在致病基因的研究中,Makorin环指蛋白3(makorin ring finger protein 3,MKRN3)、lin-28同系物A和Delta-like 1同源物等基因的功能缺失性突变,均可导致青春发育期启动时间提前,其中MKRN3的功能丧失突变是家族性CPP最常见的单基因病因之一。自2013年首次在5个CPP家族中鉴定出MKRN 3突变以来,MKRN3在青春期中的作用逐渐被发现。MKRN3属于E3泛素连接酶家族成员,在多种真核生物的中枢神经系统中表达。MKRN3可能作为E3泛素连接酶发挥作用来抑制GnRH活性。最近,越来越多的研究探讨了MKRN3在CPP中的分子作用机制,揭示了多种与MKRN3相互作用的基因及蛋白质,利如MKRN3能抑制KISS1和TAC3活性,从而影响kisspeptin和神经激肽B表达以调控GnRH分泌;MKRN3还能通过泛素化PABPC1抑制GNRH 1 mRNA翻译;另外,还有MBD3、IGF2BP1及NPTX1等靶点,它们均在MKRN3下游参与GnRH调控过程。在MKRN 3上游,miR-30能与MKRN 3基因3′-非翻译区的3个位点结合,从而阻断MKRN 3转录。本文综述了MKRN3在CPP发病过程中的作用及其分子机制方面的研究进展,有助于更好地理解CPP的发病机制,也为进一步深入研究MKRN3分子作用机制奠定了理论基础。The pathogenesis of central precocious puberty(CPP)is due to the early initiation of the function of the hypothalamic-pituitary-gonadal axis,which is driven by the gonadotrophin-releasing hormone(GnRH)from the hypothalamus.The increase of GnRH secretion will promote the secretion of gonadotropin by the pituitary gland,which leads to the development of reproductive organs and the secretion of sex hormones.The timing of puberty onset is influenced by the interaction between nutritional,environmental,and socioeconomic factors.In the study of pathogenic genes,loss-of-function mutations of MKRN3,LIN 28 and DLK 1 genes can lead to early onset of puberty,among which loss-of-function mutations of MKRN 3 are one of the most common single-gene causes of familial CPP.Since 2013,when the MKRN3 mutation was first identified in five CPP families,the role of MKRN3 in adolescence has gradually been discovered.MKRN3 is a member of the E3 ubiquitin ligase family and is expressed in the central nervous system of many eukaryotes.MKRN3 may act as an E3 ubiquitin ligase to inhibit GnRH activity.Recently,more and more studies have explored the molecular mechanism of MKRN3 in CPP,revealing a variety of genes and proteins that interact with MKRN3.For example,MKRN3 can inhibit KISS1 and TAC3 activities,thereby affecting the expression of kisspeptin and neurokinin B to regulate GnRH secretion.MKRN3 also inhibited GNRH 1 mRNA translation through PABPC1 ubiquitination.In addition,there are other targets such as MBD3,IGF2BP1 and NPTX1,all of which are involved in GnRH regulation downstream of MKRN3.Upstream of MKRN 3,miR-30 can bind to three sites in the 3'-untranslated region of the MKRN 3 gene to block MKRN 3 transcription.Here we review the role of MKRN3 in the pathogenesis of CPP and the research progress of its molecular mechanism,which will help to better understand the pathogenesis of CPP,provide new ideas and treatment methods for CPP-related fields in the future,and lay a theoretical foundation for further exploration of the molecula

关 键 词：中枢性性早熟 Makorin环指蛋白3 促性腺激素释放激素 儿童 

分 类 号：Q427[生物学—神经生物学]