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Asian Journal of Andrology 2020The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is a specific kind of asthenoteratozoospermia with a mosaic of flagellar morphological... (Review)
Review
The syndrome of multiple morphological abnormalities of the sperm flagella (MMAF) is a specific kind of asthenoteratozoospermia with a mosaic of flagellar morphological abnormalities (absent, short, bent, coiled, and irregular flagella). MMAF was proposed in 2014 and has attracted increasing attention; however, it has not been clearly understood. In this review, we elucidate the definition of MMAF from a systematical view, the difference between MMAF and other conditions with asthenoteratozoospermia or asthenozoospermia (such as primary mitochondrial sheath defects and primary ciliary dyskinesia), the knowledge regarding its etiological mechanism and related genetic findings, and the clinical significance of MMAF for intracytoplasmic sperm injection and genetic counseling. This review provides the basic knowledge for MMAF and puts forward some suggestions for further investigations.
Topics: A Kinase Anchor Proteins; Adenylate Kinase; Animals; Asthenozoospermia; Cytoskeletal Proteins; Dyneins; Genetic Counseling; Humans; Infertility, Male; Male; Microtubule Proteins; Peptide Hydrolases; Sperm Injections, Intracytoplasmic; Sperm Tail; Teratozoospermia
PubMed: 31210147
DOI: 10.4103/aja.aja_53_19 -
Cells Jul 2021The etiology of human asthenozoospermia is multifactorial. The need to unveil molecular mechanisms underlying this state of infertility is, thus, impelling. Circular...
The etiology of human asthenozoospermia is multifactorial. The need to unveil molecular mechanisms underlying this state of infertility is, thus, impelling. Circular RNAs (circRNAs) are involved in microRNA (miRNA) inhibition by a sponge activity to protect mRNA targets. All together they form the competitive endogenous RNA network (ceRNET). Recently, we have identified differentially expressed circRNAs (DE-circRNAs) in normozoospermic and asthenozoospermic patients, associated with high-quality (A-spermatozoa) and low-quality (B-spermatozoa) sperm. Here, we carried out a differential analysis of , and mRNA expression in good quality (A-spermatozoa) and low quality (B-spermatozoa) sperm fractions collected from both normozoospermic volunteers and asthenozoospermic patients. These sperm fractions are usually separated on the basis of morphology and motility parameters by a density gradient centrifugation. B-spermatozoa showed low levels of mRNAs. Thus, we identified the possible ceRNET responsible for regulating their expression by focusing on circTRIM2, circEPS15 and circRERE. With the idea that motility perturbations could be rooted in quantitative changes of transcripts in sperm, we evaluated circRNA and mRNA modulation in A-spermatozoa and B-spermatozoa after an oral amino acid supplementation known to improve sperm motility. The profiles of CRISP2, CATSPER1 and PATE1 proteins in the same fractions of sperm well matched with the transcript levels. Our data may strengthen the role of circRNAs in asthenozoospermia and shed light on the molecular pathways linked to sperm motility regulation.
Topics: Adult; Amino Acids; Asthenozoospermia; Calcium Channels; Case-Control Studies; Cell Adhesion Molecules; Dietary Supplements; Gene Expression Regulation, Developmental; Humans; Male; Membrane Proteins; MicroRNAs; RNA, Circular; Semen; Sperm Motility; Spermatozoa; Time Factors; Treatment Outcome; Young Adult
PubMed: 34440724
DOI: 10.3390/cells10081956 -
Cell Death & Disease Feb 2023The axonemal dynein arms (outer (ODA) and inner dynein arms (IDAs)) are multiprotein structures organized by light, intermediate, light intermediate (LIC), and heavy...
DNALI1 deficiency causes male infertility with severe asthenozoospermia in humans and mice by disrupting the assembly of the flagellar inner dynein arms and fibrous sheath.
The axonemal dynein arms (outer (ODA) and inner dynein arms (IDAs)) are multiprotein structures organized by light, intermediate, light intermediate (LIC), and heavy chain proteins. They hydrolyze ATP to promote ciliary and flagellar movement. Till now, a variety of dynein protein deficiencies have been linked with asthenospermia (ASZ), highlighting the significance of these structures in human sperm motility. Herein, we detected bi-allelic DNALI1 mutations [c.663_666del (p.Glu221fs)], in an ASZ patient, which resulted in the complete loss of the DNALI1 in the patient's sperm. We identified loss of sperm DNAH1 and DNAH7 rather than DNAH10 in both DNALI1 patient and Dnali1 mice, demonstrating that mammalian DNALI1 is a LIC protein of a partial IDA subspecies. More importantly, we revealed that DNALI1 loss contributed to asymmetries in the most fibrous sheath (FS) of the sperm flagellum in both species. Immunoprecipitation revealed that DNALI1 might interact with the cytoplasmic dynein complex proteins in the testes. Furthermore, DNALI1 loss severely disrupted the transport and assembly of the FS proteins, especially AKAP3 and AKAP4, during flagellogenesis. Hence, DNALI1 may possess a non-classical molecular function, whereby it regulates the cytoplasmic dynein complex that assembles the flagella. We conclude that a DNALI deficiency-induced IDAs injury and an asymmetric FS-driven tail rigid structure alteration may simultaneously cause flagellum immotility. Finally, intracytoplasmic sperm injection (ICSI) can effectively resolve patient infertility. Collectively, we demonstrate that DNALI1 is a newly causative gene for AZS in both humans and mice, which possesses multiple crucial roles in modulating flagellar assembly and motility.
Topics: Animals; Humans; Male; Mice; A Kinase Anchor Proteins; Asthenozoospermia; Axonemal Dyneins; Cytoplasmic Dyneins; Dyneins; Infertility, Male; Mammals; Mutation; Proteins; Semen; Sperm Motility; Sperm Tail
PubMed: 36792588
DOI: 10.1038/s41419-023-05653-y -
Cellular and Molecular Life Sciences :... May 2023The sperm flagellum is a specialized type of motile cilium composed of a typical "9 + 2" axonemal structure with peri-axonemal structures, such as outer dense fibers...
The sperm flagellum is a specialized type of motile cilium composed of a typical "9 + 2" axonemal structure with peri-axonemal structures, such as outer dense fibers (ODFs). This flagellar arrangement is crucial for sperm movement and fertilization. However, the association of axonemal integrity with ODFs remains poorly understood. Here, we demonstrate that mouse BBOF1 could interact with both MNS1, an axonemal component, and ODF2, an ODF protein, and is required for sperm flagellar axoneme maintenance and male fertility. BBOF1 is expressed exclusively in male germ cells from the pachytene stage onwards and is detected in sperm axoneme fraction. Spermatozoa derived from Bbof1-knockout mice exhibit a normal morphology, however, reduced motility due to the absence of certain microtubule doublets, resulting in the failure to fertilize mature oocytes. Furthermore, BBOF1 is found to interact with ODF2 and MNS1 and is also required for their stability. Our findings in mice suggest that Bbof1 could also be essential for human sperm motility and male fertility, thus is a novel potential candidate gene for asthenozoospermia diagnosis.
Topics: Animals; Male; Mice; Axoneme; Fertility; Heat-Shock Proteins; Infertility, Male; Mice, Knockout; Semen; Sperm Motility; Spermatozoa
PubMed: 37198331
DOI: 10.1007/s00018-023-04800-0 -
American Journal of Human Genetics Aug 2021Multiple morphological abnormalities of the sperm flagella (MMAF)-induced asthenoteratozoospermia is a common cause of male infertility. Previous studies have identified...
Multiple morphological abnormalities of the sperm flagella (MMAF)-induced asthenoteratozoospermia is a common cause of male infertility. Previous studies have identified several MMAF-associated genes, highlighting the condition's genetic heterogeneity. To further define the genetic causes underlying MMAF, we performed whole-exome sequencing in a cohort of 643 Chinese MMAF-affected men. Bi-allelic DNAH10 variants were identified in five individuals with MMAF from four unrelated families. These variants were either rare or absent in public population genome databases and were predicted to be deleterious by multiple bioinformatics tools. Morphological and ultrastructural analyses of the spermatozoa obtained from men harboring bi-allelic DNAH10 variants revealed striking flagellar defects with the absence of inner dynein arms (IDAs). DNAH10 encodes an axonemal IDA heavy chain component that is predominantly expressed in the testes. Immunostaining analysis indicated that DNAH10 localized to the entire sperm flagellum of control spermatozoa. In contrast, spermatozoa from the men harboring bi-allelic DNAH10 variants exhibited an absence or markedly reduced staining intensity of DNAH10 and other IDA components, including DNAH2 and DNAH6. Furthermore, the phenotypes were recapitulated in mouse models lacking Dnah10 or expressing a disease-associated variant, confirming the involvement of DNAH10 in human MMAF. Altogether, our findings in humans and mice demonstrate that DNAH10 is essential for sperm flagellar assembly and that deleterious bi-allelic DNAH10 variants can cause male infertility with MMAF. These findings will provide guidance for genetic counseling and insights into the diagnosis of MMAF-associated asthenoteratozoospermia.
Topics: Alleles; Animals; Asthenozoospermia; Disease Models, Animal; Dyneins; Homozygote; Humans; Infertility, Male; Male; Mice; Mice, Knockout; Mutation; Phenotype; Spermatozoa; Exome Sequencing
PubMed: 34237282
DOI: 10.1016/j.ajhg.2021.06.010 -
Frontiers in Medicine 2021A comprehensive literature review was performed to determine the relationship between HPV infection and infertility and the eventual role of the 9-valent vaccine for... (Review)
Review
A comprehensive literature review was performed to determine the relationship between HPV infection and infertility and the eventual role of the 9-valent vaccine for infertility prevention. The search was extended from January 1997 through July 2021. Data collected from selected articles focused on three main topics: statistical associations between HPV prevalence and assisted reproductive technology (ART) outcome, association between HPV and characteristics of semen, and associations between HPV and miscarriage. Articles that identified HPV genotypes were selected for this review to study the possible role of the 9-valent vaccine in infertility prevention. To date, there is no agreement on the implication HPV female infection has on the fertility and miscarriage rate. Although it can be stated that HPV prevalence among couples with infertility undergoing ART treatment is consistent, it does not seem to affect the performance of oocytes. Otherwise, HPV infection affects sperm parameters, in particular spermatozoa motility. When an association can be found, most cases of HR-HPV involved are those included in the 9-valent vaccine. The correlation between HPV male infection both with asthenozoospermia and increased risk of pregnancy loss could recommend the extension of anti-HPV vaccination to adolescent males along with cancer prevention. Despite the fact that the relation between 9-valent HPV genotypes involved in female infection and miscarriage/infertility is not clear, the impact of this virus on health reproduction is evident. Considering this, the importance of HPV vaccination in adolescent females is confirmed. A vaccine efficacy study could be useful to confirm the importance of primary prevention for couple reproductive health.
PubMed: 34485336
DOI: 10.3389/fmed.2021.700792 -
BMC Medical Genomics Dec 2022Asthenozoospermia is a troublesome disease experienced by men in their reproductive years, but its exact etiology remains unclear. To address this problem, this study...
BACKGROUND
Asthenozoospermia is a troublesome disease experienced by men in their reproductive years, but its exact etiology remains unclear. To address this problem, this study aims to identify the hub genes and crucial pathways in asthenozoospermia.
METHODS
We screened two Gene Expression Omnibus (GEO) datasets (GSE92578 and GSE22331) to extract the differentially expressed genes (DEGs) between normozoospermic and asthenozoospermic men using the "Limma" package. Gene enrichment analyses of the DEGs were conducted using the "clusterProfiler" R package. The protein-protein interaction (PPI) network was then established using the STRING database. A miRNA-transcription factor-gene network was constructed based on the predicted results of hub genes using the RegNetwork database. The expression of four hub genes in asthenozoospermia and normal samples were verified using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting.
RESULTS
We identified 271 DEGs, which included 218 upregulated and 53 downregulated in two asthenozoospermia datasets. These DEGs were observed to be markedly enriched in pathways with cell growth and embryonic organ development, phospholipase D signaling pathway, cGMP-PKG signaling pathway, and Wnt signaling pathway. The most significant genes were identified, including COPS7A, CUL3, KLHL7, NEDD4. We then constructed regulatory networks of these genes, miRNAs, and transcription factors. Finally, we found that the COPS7A was significantly upregulated in patients with asthenozoospermia, but CUL3, KLHL7 and NEDD4 were significantly downregulated compared with normal samples.
CONCLUSION
We applied bioinformatics methods to analyze the DEGs of asthenozoospermia based on the GEO database and identified the novel crucial genes and pathways in this disease. Our findings may provide novel insights into asthenozoospermia and identify new clues for the potential treatment of this disease.
Topics: Humans; Male; Asthenozoospermia; Computational Biology; COP9 Signalosome Complex; Gene Expression Profiling; Gene Regulatory Networks; MicroRNAs; Protein Interaction Maps; Transcription Factors
PubMed: 36471356
DOI: 10.1186/s12920-022-01407-5 -
Journal, Genetic Engineering &... Jan 2021Asthenozoospermia is a chief reason for male seminal pathologies with an impression of around 19% of infertile patients. Spermatozoa mitochondrial DNA variations seem to...
BACKGROUND
Asthenozoospermia is a chief reason for male seminal pathologies with an impression of around 19% of infertile patients. Spermatozoa mitochondrial DNA variations seem to link with low sperm motility. The objective of the study was to assess the relation between mitochondrial mutations and male sterility, especially in asthenozoospermia. The patient semen samples were investigated by studying the sperm physical characters; motility, viability, and morphological parameters were then classified into normozoospermia and asthenozoospermia. In addition, the level of malondialdehyde (MDA) as a bio-indicator of lipid peroxidation, seminal fructose, and total antioxidant capacity (TAC) were estimated. For molecular analysis, DNA from the semen samples was extracted using a DNA extraction kit. ND1, ND2, and ATPase6 genes were amplified by using a specific primer. After the purification procedure, each PCR product was sequenced to identify the single nucleotide polymorphisms (SNPs) in selected genes.
RESULTS
A significant negative correlation between seminal plasma malondialdehyde levels and sperm motility was detected. Meanwhile, TAC analysis revealed significantly lower activity (p ≤ 0.05) in the sample of asthenozoospermic than in normozoospermic men. As regards the seminal plasma fructose, there was no significant difference in the fructose level of normozoospermia and asthenozoospermia cases. At the molecular level, 31 diverse nucleotide substitutions were recognized in mitochondrial DNA. Only ten (10) mutations led to amino acid transformation: four have deleterious effects, four are benign, and the other two have conflicting effectiveness.
CONCLUSIONS
This study is the first in Egypt that is concerned with studying the relationship between the mitochondrial DNA mutations in human spermatozoa of asthenozoospermic patients and fertility. The results displayed scientific indications evidenced that there is an association between mitochondrial mutations and male infertility.
PubMed: 33459881
DOI: 10.1186/s43141-020-00111-0 -
JCI Insight Feb 2023Multiple morphological abnormalities of the sperm flagella (MMAF) are the most severe form of asthenozoospermia due to impaired axoneme structure in sperm flagella....
Multiple morphological abnormalities of the sperm flagella (MMAF) are the most severe form of asthenozoospermia due to impaired axoneme structure in sperm flagella. Dynein arms are necessary components of the sperm flagellar axoneme. In this study, we recruited 3 unrelated consanguineous Pakistani families with multiple MMAF-affected individuals, who had no overt ciliary symptoms. Whole-exome sequencing and Sanger sequencing identified 2 cilia and flagella associated protein 57 (CFAP57) loss-of-function mutations (c.2872C>T, p. R958*; and c.2737C>T, p. R913*) recessively segregating with male infertility. A mouse model mimicking the mutation (c.2872C>T) was generated and recapitulated the typical MMAF phenotype of CFAP57-mutated individuals. Both CFAP57 mutations caused loss of the long transcript-encoded CFAP57 protein in spermatozoa from MMAF-affected individuals or from the Cfap57-mutant mouse model while the short transcript was not affected. Subsequent examinations of the spermatozoa from Cfap57-mutant mice revealed that CFAP57 deficiency disrupted the inner dynein arm (IDA) assembly in sperm flagella and that single-headed IDAs were more likely to be affected. Thus, our study identified 2 pathogenic mutations in CFAP57 in MMAF-affected individuals and reported a conserved and pivotal role for the long transcript-encoded CFAP57 in IDAs' assembly and male fertility.
Topics: Animals; Humans; Male; Mice; Cilia; Dyneins; Flagella; Semen; Microtubule-Associated Proteins; Loss of Function Mutation
PubMed: 36752199
DOI: 10.1172/jci.insight.166869 -
International Journal of Molecular... Sep 2022This study is to analyze the effect of C-type natriuretic peptide (CNP) on sperm motility of asthenozoospermia and explore the influence mechanism of CNP on the...
This study is to analyze the effect of C-type natriuretic peptide (CNP) on sperm motility of asthenozoospermia and explore the influence mechanism of CNP on the reproductive system and sperm motility. Our results showed that the concentration of CNP in asthenospermia patients' semen was lower than in normal people's. The motility of sperm could be improved markedly by CNP and 8-Br-cGMP, while the effect of CNP was inhibited by NPR-B antagonist and KT5823. In the asthenozoospermia mouse model induced by CTX, CNP injection could improve sperm motility in the epididymis, alleviate tissue damage in the testes and epididymis, and increase testosterone levels. The asthenospermia mouse model showed high activity of MDA and proinflammatory factors (TNF-α, IL-6), as well as low expression of antioxidants (SOD, GSH-Px, CAT) in the testis and epididymis, but this situation could be significantly ameliorated after being treated with CNP. Those studies indicated that the concentration of CNP in the semen of asthenospermia patients is lower than in normal people and could significantly promote sperm motility through the NPR-B/cGMP pathway. In the asthenospermia mouse model induced by CTX, CNP can alleviate the damage of cyclophosphamide to the reproductive system and sperm motility. The mechanism may involve increasing testosterone and reducing ROS and proinflammatory factors to damage the tissue and sperm.
Topics: Animals; Antioxidants; Asthenozoospermia; Cyclophosphamide; Humans; Interleukin-6; Male; Mice; Natriuretic Peptide, C-Type; Reactive Oxygen Species; Semen; Sperm Motility; Spermatozoa; Superoxide Dismutase; Testosterone; Tumor Necrosis Factor-alpha
PubMed: 36142279
DOI: 10.3390/ijms231810370