title: Functional study of one nucleotide mutation in pri-miR-125a coding region which related to recurrent pregnancy loss.
abstract: MicroRNAs (miRNAs) are short non-coding RNAs which modulate gene expression by binding to complementary segments present in the 3'UTR of the mRNAs of protein coding genes. MiRNAs play very important roles in maintaining normal human body physiology conditions, meanwhile, abnormal miRNA expressions have been found related to many human diseases spanning from psychiatric disorders to malignant cancers. Recently, emerging reports have indicated that disturbed miRNAs expression contributed to the pathogenesis of recurrent pregnancy loss (RPL). In this study, we identified a new mutation site (+29A>G, position relative to pre-miR-125a) by scanning pri-miR-125a coding region in 389 Chinese Han RPL patients. This site was co-existed with two polymorphisms (rs12976445 and rs41275794) in patients heterogeneously and changed the predicted secondary structures of pri-miR-125a. Subsequent in vitro analysis indicated that the A>G mutation reduced mature miR-125a expression, and further led to less efficient inhibition of verified target genes. Functional analysis showed that mutant pri-mir-125a can enhance endometrial stromal cells (ESCs) invasive capacity and increase the sensitivity of ESCs cells to mifepristone. Moreover, we further analyzed the possible molecular mechanism by RIP-chip assay and found that mutant pri-mir-125a disturbed the expression of miR-125a targetome, the functions of which includes embryonic development, cell proliferation, migration and invasion. These data suggest that A>G mutation in pri-miR-125a coding region contributes to the genetic predisposition to RPL by disordering the production of miR-125a, which consequently meddled in gene regulatory network between mir-125a and mRNA.
authors.affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China; Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biotechnology, School of Basic Medical Science, Ningxia Medical University, Yinchuan, Ningxia, China.
authors.forename: Zheng-Hao
authors.initials: ZH
authors.lastname: Huo
authors.affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Liu
authors.affiliation: Affiliated hospital of medical college of Qing Dao university, Qingdao, China.
authors.forename: Shi-Guo
authors.initials: SG
authors.lastname: Liu
authors.affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China; Graduate School; Peking Union Medical College, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China; Graduate School; Peking Union Medical College, Beijing, China.
authors.forename: Kun-Lun
authors.initials: KL
authors.lastname: Yin
authors.affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China; Graduate School; Peking Union Medical College, Beijing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China; Graduate School; Peking Union Medical College, Beijing, China.
authors.forename: Hong-Fei
authors.initials: HF
authors.lastname: Xia
mesh_terms: D020413:3' Untranslated Regions; D000026:Abortion, Habitual / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D020871:RNA Stability; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D015735:Mifepristone