title: Novel WT1 Missense Mutations in Han Chinese Women with Premature Ovarian Failure.
abstract: Premature ovarian failure (POF) is a heterogeneous disease. Though dozens of candidate genes have been identified for the genetic etiology of POF, it is largely unexplained in majority of patients. Recently, Wt1(+/R394W) mice was found to present POF-like phenotype, which indicates that WT1 might be a plausible candidate gene for non-syndromic POF. The coding region of WT1 gene was screened in 384 patients with POF and 6 novel variations were identified, including two missense mutations (p. Pro126Ser in exon1 and p. Arg370His in exon7) and four intronic variants (c.647-27C > T, c.647-13G > C, c.647-13G > A in intron1 and c.950 + 14T > C in intron 4). In vitro experiments showed that both mutant p. Pro126Ser and p. Arg370His repressed the expression of Amh and Cdh1, and induced the expression of Fshr and Cyp19 in mRNA level (P < 0.05). The expression changes of AMH, FSHR, CYP19 and CDH1 were confirmed by western blot. These genes (AMH, FSHR, CYP19 and CDH1) are required for granular cells (GCs) proliferation, differentiation and oocyte-GCs interaction. The novel mutant p. P126S and p. R370H in the WT1 gene potentially impaired GCs differentiation and oocyte-GCs interaction, which might result in loss of follicles prematurely. Therefore, WT1 is a plausible causal gene for POF.
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, Shandong, China.
authors.forename: Huidan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, Shandong, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of Zoology, Chinese Academy of Sciences, State Key Laboratory of Reproduction Biology, Beijing, China.|Department of Toxicology, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Zoology, Chinese Academy of Sciences, State Key Laboratory of Reproduction Biology, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Li
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, Shandong, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, Shandong, China.|Center for Reproductive Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zi-Jiang
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D002681:China; D005260:Female; D023061:Gene Order; D016162:Genes, Wilms Tumor; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D022821:RNA Splice Sites; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D022821:RNA Splice Sites