Novel ACTL7A variants in males lead to fertilization failure and male infertility.
ACTL7A
PLCζ1
fertilization failure
intracytoplasmic sperm injection
male infertility
Journal
Andrology
ISSN: 2047-2927
Titre abrégé: Andrology
Pays: England
ID NLM: 101585129
Informations de publication
Date de publication:
22 Nov 2023
22 Nov 2023
Historique:
revised:
05
09
2023
received:
08
04
2023
accepted:
20
10
2023
medline:
22
11
2023
pubmed:
22
11
2023
entrez:
22
11
2023
Statut:
aheadofprint
Résumé
Total fertilization failure occurs in 1%-3% of all intracytoplasmic sperm injection cycles. Genetic defects are found to be crucial causes responsible for total fertilization failure after intracytoplasmic sperm injection. However, the reported genes only elucidate a small proportion of total fertilization failure cases, and more genetic defects are required to be explored. To investigate the genetic causes of male-related fertilization failure and explore the potential underlying mechanism. Whole-exome sequencing was performed on male patients suffering from fertilization failure, and Sanger sequencing was used to confirm the detected mutations. The effects of genetic mutations on protein function were analyzed using bioinformatic tools and immunofluorescence assays. Two males with ACTL7A mutations were enrolled. One carried two compound heterozygous mutations (c.1118G>A:p.R373H; c.1204G>A:p.G402S), the other had a homozygous mutation (c.1117C>T:p.R373C) and was from a consanguineous family with a recessive inheritance pattern. All the variants were located in the actin domain and were predicted to be pathogenic, affecting the number of hydrogen bonds or the arrangement of nearby protein structures. Furthermore, the protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting, confirming the pathogenicity of the variants. In addition, the phospholipase C zeta 1 was barely absent, and acrosome peanut agglutinin signals were attenuated and unevenly distributed, indicating acrosome dysfunction. In addition, intracytoplasmic sperm injection with artificial oocyte activation treatment could increase the fertilization rate in oocytes injected with affected spermatozoa. Our study identified three ACTL7A pathogenic missense mutations in two males with fertilization failure. It expands the mutational and phenotypic spectrum of ACTL7A gene and provides information on the pathogenesis and therapeutic strategies of fertilization defects induced by ACTL7A pathogenic variants. ACTL7A variants affected the expression and localization of actin-like protein 7A in the affected spermatozoa and subsequently decreased the expression of phospholipase C zeta 1, which caused fertilization failure and male infertility.
Sections du résumé
BACKGROUND
BACKGROUND
Total fertilization failure occurs in 1%-3% of all intracytoplasmic sperm injection cycles. Genetic defects are found to be crucial causes responsible for total fertilization failure after intracytoplasmic sperm injection. However, the reported genes only elucidate a small proportion of total fertilization failure cases, and more genetic defects are required to be explored.
OBJECTIVE
OBJECTIVE
To investigate the genetic causes of male-related fertilization failure and explore the potential underlying mechanism.
MATERIAL AND METHODS
METHODS
Whole-exome sequencing was performed on male patients suffering from fertilization failure, and Sanger sequencing was used to confirm the detected mutations. The effects of genetic mutations on protein function were analyzed using bioinformatic tools and immunofluorescence assays.
RESULTS
RESULTS
Two males with ACTL7A mutations were enrolled. One carried two compound heterozygous mutations (c.1118G>A:p.R373H; c.1204G>A:p.G402S), the other had a homozygous mutation (c.1117C>T:p.R373C) and was from a consanguineous family with a recessive inheritance pattern. All the variants were located in the actin domain and were predicted to be pathogenic, affecting the number of hydrogen bonds or the arrangement of nearby protein structures. Furthermore, the protein expression of actin-like protein 7A was absent in affected spermatozoa by using immunofluorescence staining and western blotting, confirming the pathogenicity of the variants. In addition, the phospholipase C zeta 1 was barely absent, and acrosome peanut agglutinin signals were attenuated and unevenly distributed, indicating acrosome dysfunction. In addition, intracytoplasmic sperm injection with artificial oocyte activation treatment could increase the fertilization rate in oocytes injected with affected spermatozoa.
DISCUSSION
CONCLUSIONS
Our study identified three ACTL7A pathogenic missense mutations in two males with fertilization failure. It expands the mutational and phenotypic spectrum of ACTL7A gene and provides information on the pathogenesis and therapeutic strategies of fertilization defects induced by ACTL7A pathogenic variants.
CONCLUSION
CONCLUSIONS
ACTL7A variants affected the expression and localization of actin-like protein 7A in the affected spermatozoa and subsequently decreased the expression of phospholipase C zeta 1, which caused fertilization failure and male infertility.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Key Research and Development Project
ID : 2021YFC2700603
Organisme : National Key Research and Development Project
ID : 2022YFC2702503
Organisme : Key Research of Huazhong University of Science and Technology, Tongji Hospital
ID : 2022A20
Informations de copyright
© 2023 American Society of Andrology and European Academy of Andrology.
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