2. Academic Validation
  3. Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice

Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice

  • Am J Hum Genet. 2021 Mar 4;108(3):469-481. doi: 10.1016/j.ajhg.2021.02.004.
Jing Dai 1,  Tianlei Zhang 2,  Jing Guo 2,  Qinwei Zhou 3,  Yifan Gu 4,  Jue Zhang 2,  Liang Hu 4,  Yurong Zong 3,  Juan Song 3,  Shuoping Zhang 3,  Can Dai 2,  Fei Gong 4,  Guangxiu Lu 5,  Wei Zheng 6,  Ge Lin 7
Affiliations

Affiliations

  • 1 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China; Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410078, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China.
  • 2 Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410078, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China; Hunan Normal University, Changsha 410013, China.
  • 3 Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410078, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China.
  • 4 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China; Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410078, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China; Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha 410078, China.
  • 5 Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410078, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China; Hunan Normal University, Changsha 410013, China; Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha 410078, China.
  • 6 Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410078, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China; Hunan Normal University, Changsha 410013, China. Electronic address: [email protected].
  • 7 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China; Reproductive and Genetic Hospital of CITIC-XIANGYA, Changsha 410078, China; Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha 410078, China; Laboratory of Reproductive and Stem Cell Engineering, National Health and Family Planning Commission, Changsha 410078, China. Electronic address: [email protected].
PMID: 33626338 DOI: 10.1016/j.ajhg.2021.02.004
Abstract

Total fertilization failure (TFF) can occur during in vitro fertilization (IVF) treatments, even following intracytoplasmic sperm injection (ICSI). Various male or female factors could contribute to TFF. Increasing evidence suggested that genetic variations in PLCZ1, which encodes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCζ), is involved in oocyte activation and is a key male factor in TFF. In the present study, we explored the genetic variants in male individuals that led to TFF. A total of 54 couples with TFF or poor fertilization (fertilization rate < 20%) were screened, and 21 couples were determined to have a male infertility factor by the mouse oocyte activation test. Whole-exome sequencing of these 21 male individuals identified three homozygous pathogenic variants in ACTL9 (actin like 9) in three individuals. ACTL9 variations led to abnormal ultrastructure of the perinuclear theca (PT), and PLCζ was absent in the head and present in the neck of the mutant sperm, which contributed to failed normal calcium oscillations in oocytes and subsequent TFF. The key roles of ACTL9 in the PT structure and TFF after ICSI were further confirmed in an Actl9-mutated mouse model. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF and achieved live births in a couple with an ACTL9 variant. These findings identified the role of ACTL9 in the PT structure and the correct localization of PLCζ. The results also provide a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization.

Keywords

ACTL9; PLCζ; assisted oocyte activation; fertilization failure; male factor; mouse model; perinuclear theca; poor fertilization; whole-exome sequencing.

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