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Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects.
Li, Qun; Zhao, Lin; Zeng, Yang; Kuang, Yanping; Guan, Yichun; Chen, Biaobang; Xu, Shiru; Tang, Bin; Wu, Ling; Mao, Xiaoyan; Sun, Xiaoxi; Shi, Juanzi; Xu, Peng; Diao, Feiyang; Xue, Songguo; Bao, Shihua; Meng, Qingxia; Yuan, Ping; Wang, Wenjun; Ma, Ning; Song, Di; Xu, Bei; Dong, Jie; Mu, Jian; Zhang, Zhihua; Fan, Huizhen; Gu, Hao; Li, Qiaoli; He, Lin; Jin, Li; Wang, Lei; Sang, Qing.
  • Li Q; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Zhao L; Human Phenome Institute, Fudan University, Shanghai, 200438, China.
  • Zeng Y; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Kuang Y; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Guan Y; Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, 200011, China.
  • Chen B; Department of Reproductive Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • Xu S; NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, Shanghai, 200032, China.
  • Tang B; Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, 518001, Guangdong, China.
  • Wu L; Reproductive Medicine Center, The First People's Hospital of Changde City, Changde, 415000, China.
  • Mao X; Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, 200011, China.
  • Sun X; Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, 200011, China.
  • Shi J; Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
  • Xu P; Reproductive Medicine Center, Northwest Women's and Children's Hospital, Xi'an, 710000, China.
  • Diao F; Hainan Jinghua Hejing Hospital for Reproductive Medicine, Haikou, 570125, China.
  • Xue S; Reproductive Medicine Center, Jiangsu Province Hospital, Nanjing, 210036, China.
  • Bao S; Reproductive Medicine Center, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, China.
  • Meng Q; Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China.
  • Yuan P; Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215000, China.
  • Wang W; IVF Center, Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
  • Ma N; IVF Center, Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
  • Song D; Reproductive Medical Center, Maternal and Child Health Care Hospital of Hainan Province, Haikou, 570206, Hainan Province, China.
  • Xu B; Naval Medical University, Changhai Hospital, Shanghai, China.
  • Dong J; Reproductive Medicine Centre, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, China.
  • Mu J; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Zhang Z; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Fan H; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Gu H; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Li Q; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • He L; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • Jin L; Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • Wang L; State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, China.
  • Sang Q; Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China. wangleiwanglei@fudan.edu.cn.
Genome Biol ; 24(1): 68, 2023 04 06.
Article en En | MEDLINE | ID: mdl-37024973
ABSTRACT

BACKGROUND:

Oocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated.

RESULTS:

To decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent-child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a (TUBA4A), which shows the most significant enrichment of DNMs in the infertile parent-child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A.

CONCLUSIONS:

Our findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Infertilidad Femenina Tipo de estudio: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Año: 2023 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Infertilidad Femenina Tipo de estudio: Diagnostic_studies / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans / Pregnancy Idioma: En Año: 2023 Tipo del documento: Article