Disruption in
            <i>ACTL7A</i>
            causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest

Xin, Aijie; Qu, Ronggui; Chen, Guowu; Zhang, Ling; Chen, Junling; Tao, Chengqiu; Fu, Jing; Tang, Jianan; Ru, Yanfei; Chen, Ying; Peng, Xiandong; Shi, Huijuan; Zhang, Feng; Sun, Xiaoxi

doi:10.1126/sciadv.aaz4796

Cited by 72 publications

(77 citation statements)

References 29 publications

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“…[14][15][16][17][18][19] Recently, ACTL7A was added as another male factor associated with TFF due to reduced expression and abnormal localization of PLCz. 23 In the present study, we investigated 21 male individuals who underwent at least one ICSI cycle without successful fertilization and identified three homozygous pathogenic variants in ACTL9 impacting the ultrastructure of the PT, ultimately leading to absent or abnormal localization of PLCz with subsequent oocyte activation failure and TFF.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22] Most recently, it was reported that pathogenic variants in ACTL7A (MIM: 604303) led to reduced expression and abnormal localization of PLCz, thereby identifying this genetic variant as a potential cause of TFF. 23 In the present study, we used whole-exome sequencing (WES) and identified three homozygous variants in ACTL9 (actin like 9 [HGNC: 28494, GenBank: NM_178525.5]) in males from 21 couples suffering from TFF or poor fertilization. Our results suggest that mutant ACTL9 has weakened or lost interaction with ACTL7A that causes abnormal localization of PLCz and a loosened PT structure, ultimately leading to failure of oocyte activation.…”

Section: Introductionmentioning

confidence: 99%

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

Dai

Zhang

Guo

et al. 2021

The American Journal of Human Genetics

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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 (PLCz), 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 PLCz 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 PLCz. The results also provide a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Dai

Zhang

Guo

et al. 2021

The American Journal of Human Genetics

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“…The semen analysis was based on the standard of the fifth edition of the WHO guidelines. A normal semen sample should be equipped with at least a concentration of 15 × 10 6 /ml, a total motility of 40%, and a normal morphology rate of 4% ( Xin et al, 2020 ). Standard density-gradient centrifugation was performed for sperm selection as previously described ( Huang et al, 2015 ).…”

Section: Methodsmentioning

confidence: 99%

A Novel Assisted Oocyte Activation Method Improves Fertilization in Patients With Recurrent Fertilization Failure

Wang

Zhu

Liu

et al. 2021

Front. Cell Dev. Biol.

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Total fertilization failure (TFF) occurs in 1–3% of total intracytoplasmic sperm injection (ICSI) cycles and can reoccur in subsequent cycles. Despite the high success rate with the application of assisted oocyte activation (AOA), there is still a small number of couples who cannot obtain fertilized eggs after conventional calcium (Ca2+) ionophores-based ICSI-AOA. Six couples experiencing repeated TFF or low fertilization (<10%) after ICSI and conventional ICSI-AOA were enrolled in this study. Compared with the regular ICSI group and the conventional ICSI-AOA group, the new AOA method, a combination of cycloheximide (CHX) and ionomycin, can significantly increase the fertilization rate from less than 10 up to approximately 50% in most cases. The normal distribution of sperm-related oocyte activation factor phospholipase C zeta (PLCζ1) in the sperms of the cases indicated the absence of an aberrant Ca2+ signaling activation. The results of the whole-embryo aneuploidies analysis indicated that oocytes receiving the novel AOA treatment had the potential to develop into blastocysts with normal karyotypes. Our data demonstrated that CHX combined with ionomycin was able to effectively improve the fertilization rate in the majority of patients suffering from TFF. This novel AOA method had a potential therapeutic effect on those couples experiencing TFF, even after conventional AOA, which may surmount the severe fertilization deficiencies in patients with a repeated low fertilization or TFF.

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“…Loos-of-function cause spermatogenic or early embryonic arrest/failure. Recently, was observed a reduced expression and abnormal localization of phospholipase C zeta (PLCζ) in both ACTL7A/Actl7a-mutated men and mice [ 25 , 47 , 50 ].…”

Section: Crispr/cas9 and Infertilitymentioning

confidence: 99%

Mini-Review Regarding the Applicability of Genome Editing Techniques Developed for Studying Infertility

et al. 2021

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Infertility is a highly debated topic today. It has been long hypothesized that infertility has an idiopathic cause, but recent studies demonstrated the existence of a genetic substrate. Fortunately, the methods of editing the human genome proven to be revolutionary. Following research conducted, we identified a total of 21 relevant studies; 14 were performed on mice, 5 on zebrafish and 2 on rats. We concluded that over forty-four genes in total are dispensable for fertility in both sexes without affecting host homeostasis. However, there are genes whose loss-of-function induces moderate to severe phenotypic changes in both sexes. There were situations in which the authors reported infertility, exhibited by the experimental model, or other pathologies such as cryptorchidism, cataracts, or reduced motor activity. Overall, zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 are techniques that offer a wide range of possibilities for studying infertility, even to create mutant variants. It can be concluded that ZFNs, TALENs, and CRISPR/Cas9 are crucial tools in biomedical research.

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Disruption in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest

Cited by 72 publications

References 29 publications

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

A Novel Assisted Oocyte Activation Method Improves Fertilization in Patients With Recurrent Fertilization Failure

Mini-Review Regarding the Applicability of Genome Editing Techniques Developed for Studying Infertility

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