2. Academic Validation
  3. Homozygous Mutations in BTG4 Cause Zygotic Cleavage Failure and Female Infertility

Homozygous Mutations in BTG4 Cause Zygotic Cleavage Failure and Female Infertility

  • Am J Hum Genet. 2020 Jul 2;107(1):24-33. doi: 10.1016/j.ajhg.2020.05.010.
Wei Zheng 1,  Zhou Zhou 2,  Qianqian Sha 3,  Xiangli Niu 4,  Xiaoxi Sun 5,  Juanzi Shi 6,  Lei Zhao 1,  Shuoping Zhang 1,  Jing Dai 1,  Sufen Cai 1,  Fei Meng 1,  Liang Hu 7,  Fei Gong 7,  Xiaoran Li 4,  Jing Fu 5,  Rong Shi 6,  Guangxiu Lu 7,  Biaobang Chen 8,  Hengyu Fan 9,  Lei Wang 10,  Ge Lin 11,  Qing Sang 12
Affiliations

Affiliations

  • 1 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China.
  • 2 Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology and Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China.
  • 3 Fertility Preservation Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China.
  • 4 Reproductive Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China.
  • 5 Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China.
  • 6 Reproductive Medicine Center, Shaanxi Maternal and Child Care Service Center, Shaanxi, 710069, China.
  • 7 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China; Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China; Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, 410078, China.
  • 8 NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai, 200032, China.
  • 9 Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
  • 10 Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology and Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China; Shanghai Center for Women and Children's Health, Shanghai, 200062, China.
  • 11 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, 410078, China; Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410078, China; Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha, 410078, China. Electronic address: [email protected].
  • 12 Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology and Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
PMID: 32502391 DOI: 10.1016/j.ajhg.2020.05.010
Abstract

Zygotic cleavage failure (ZCF) is a unique early embryonic phenotype resulting in female infertility and recurrent failure of in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). With this phenotype, morphologically normal oocytes can be retrieved and successfully fertilized, but they fail to undergo cleavage. Until now, whether this phenotype has a Mendelian inheritance pattern and which underlying genetic factors play a role in its development remained to be elucidated. B cell translocation gene 4 (BTG4) is a key adaptor of the CCR4-NOT deadenylase complex, which is involved in maternal mRNA decay in mice, but no human diseases caused by mutations in BTG4 have previously been reported. Here, we identified four homozygous mutations in BTG4 (GenBank: NM_017589.4) that are responsible for the phenotype of ZCF, and we found they followed a recessive inheritance pattern. Three of them-c.73C>T (p.Gln25Ter), c.1A>G (p.?), and c.475_478del (p.Ile159LeufsTer15)-resulted in complete loss of full-length BTG4 protein. For c.166G>A (p.Ala56Thr), although the protein level and distribution of mutant BTG4 was not altered in zygotes from affected individuals or in HeLa cells, the interaction between BTG4 and CNOT7 was abolished. In vivo studies further demonstrated that the process of maternal mRNA decay was disrupted in the zygotes of the affected individuals, which provides a mechanistic explanation for the phenotype of ZCF. Thus, we provide evidence that ZCF is a Mendelian phenotype resulting from mutations in BTG4. These findings contribute to our understanding of the role of BTG4 in human early embryonic development and provide a genetic marker for female infertility.

Keywords

BTG4; female infertility; mutation; zygotic cleavage failure.

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