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Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility.American Journal of Human Genetics Feb 2021Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent...
Asthenoteratozoospermia characterized by multiple morphological abnormalities of the flagella (MMAF) has been identified as a sub-type of male infertility. Recent progress has identified several MMAF-associated genes with an autosomal recessive inheritance in human affected individuals, but the etiology in approximately 40% of affected individuals remains unknown. Here, we conducted whole-exome sequencing (WES) and identified hemizygous missense variants in the X-linked CFAP47 in three unrelated Chinese individuals with MMAF. These three CFAP47 variants were absent in human control population genome databases and were predicted to be deleterious by multiple bioinformatic tools. CFAP47 encodes a cilia- and flagella-associated protein that is highly expressed in testis. Immunoblotting and immunofluorescence assays revealed obviously reduced levels of CFAP47 in spermatozoa from all three men harboring deleterious missense variants of CFAP47. Furthermore, WES data from an additional cohort of severe asthenoteratozoospermic men originating from Australia permitted the identification of a hemizygous Xp21.1 deletion removing the entire CFAP47 gene. All men harboring hemizygous CFAP47 variants displayed typical MMAF phenotypes. We also generated a Cfap47-mutated mouse model, the adult males of which were sterile and presented with reduced sperm motility and abnormal flagellar morphology and movement. However, fertility could be rescued by the use of intra-cytoplasmic sperm injections (ICSIs). Altogether, our experimental observations in humans and mice demonstrate that hemizygous mutations in CFAP47 can induce X-linked MMAF and asthenoteratozoospermia, for which good ICSI prognosis is suggested. These findings will provide important guidance for genetic counseling and assisted reproduction treatments.
Topics: Animals; Asthenozoospermia; Cohort Studies; Female; Gene Deletion; Genes, X-Linked; Hemizygote; Humans; Infertility, Male; Male; Mice, Inbred C57BL; Mutation; Mutation, Missense; Pedigree; Phenotype; Sperm Injections, Intracytoplasmic; Sperm Motility; Sperm Tail; Spermatozoa; Exome Sequencing; Mice
PubMed: 33472045
DOI: 10.1016/j.ajhg.2021.01.002 -
Journal of Controlled Release :... Oct 2023Asthenozoospermia, characterized by poor sperm motility, is a common cause of male infertility. Improving energy metabolism and alleviating oxidative stress through drug...
Asthenozoospermia, characterized by poor sperm motility, is a common cause of male infertility. Improving energy metabolism and alleviating oxidative stress through drug regimens are potential therapeutic strategies. In this study, we observed upregulated miR-24-3p levels in asthenozoospermia spermatozoa, contributing to energy metabolism disorder and oxidative stress by reducing GSK3β expression. Thus, reducing miR-24-3p levels using drugs is expected to improve sperm motility. The blood-testis barrier (BTB) protects the testis from xenobiotics and drugs. In this study, we found that Sertoli cell-derived small extracellular vesicles (SC-sEV) can traverse the BTB and enter germ cells. We successfully loaded miR-24-3p inhibitor into SC-sEV, creating the nano-drug SC-sEV@miR-24-3p inhibitor, which effectively delivers miR-24-3p inhibitor into germ cells. In a gossypol-induced mouse asthenozoospermia model, administration of SC-sEV@miR-24-3p inhibitor significantly improved sperm motility, in vitro fertilization success, and blastocyst formation rates. As anticipated, it also improved the litter size of asthenozoospermia mice. These results suggest that SC-sEV@miR-24-3p inhibitor holds promise as a potential clinical treatment for asthenospermia.
Topics: Humans; Male; Mice; Animals; Sertoli Cells; Asthenozoospermia; Sperm Motility; Blood-Testis Barrier; Semen; Spermatozoa; Germ Cells; MicroRNAs; Extracellular Vesicles
PubMed: 37595666
DOI: 10.1016/j.jconrel.2023.08.031 -
Best Practice & Research. Clinical... Dec 2020Asthenozoospermia (AZS), defined by reduced motility or absent sperm motility, is one of the main causes of male infertility. This condition may be divided into isolated... (Review)
Review
Asthenozoospermia (AZS), defined by reduced motility or absent sperm motility, is one of the main causes of male infertility. This condition may be divided into isolated AZS in the absence of other symptoms and syndromic AZS, which is characterized by several concurrent clinical symptoms. Sperm motility depends on fully functional flagellum, energy availability, and the crosstalk of several signaling pathways; therefore, mutations in genes involved in flagellar assembly and motile regulation can cause AZS. Thus, it is crucial to understand the genetic causes and mechanisms contributing to AZS. In this review, we summarize the current knowledge about the particular genes and mechanisms involved in intact flagellum, energy availability, and signaling transduction that could cause human AZS and discuss the respective gene defects known to be responsible for these abnormalities. Additionally, we discuss intracytoplasmic sperm injection outcomes and offspring health where available in these cases.
Topics: Asthenozoospermia; Energy Metabolism; Humans; Infertility, Male; Male; Mutation; Sperm Motility; Spermatozoa
PubMed: 33191078
DOI: 10.1016/j.beem.2020.101472 -
Human Genetics Jun 2023Asthenozoospermia is one of the main factors leading to male infertility, but the genetic mechanisms have not been fully elucidated. Variants in the androglobin (ADGB)...
Asthenozoospermia is one of the main factors leading to male infertility, but the genetic mechanisms have not been fully elucidated. Variants in the androglobin (ADGB) gene were identified in an infertile male characterized by asthenozoospermia. The variants disrupted the binding of ADGB to calmodulin. Adgb male mice were infertile due to reduced sperm concentration (< 1 × 10 /mL) and motility. Spermatogenesis was also abnormal, with malformation of both elongating and elongated spermatids, and there was an approximately twofold increase in apoptotic cells in the cauda epididymis. These exacerbated the decline in sperm motility. It is surprising that ICSI with testicular spermatids allows fertilization and eventually develops into blastocyst. Through mass spectrometry, we identified 42 candidate proteins that are involved in sperm assembly, flagella formation, and sperm motility interacting with ADGB. In particular, CFAP69 and SPEF2 were confirmed to bind to ADGB. Collectively, our study suggests the potential important role of ADGB in human fertility, revealing its relevance to spermatogenesis and infertility. This expands our knowledge of the genetic causes of asthenozoospermia and provides a theoretical basis for using ADGB as an underlying genetic marker for infertile males.
Topics: Animals; Humans; Male; Mice; Asthenozoospermia; Infertility, Male; Semen; Sperm Motility; Spermatozoa
PubMed: 36995441
DOI: 10.1007/s00439-023-02546-0 -
Actas Urologicas Espanolas Jun 2020Male infertility accounts for 50% of the causes of infertile couples, being more than 30% of unknown etiology. In these cases, empiric treatment can be an option prior... (Review)
Review
Male infertility accounts for 50% of the causes of infertile couples, being more than 30% of unknown etiology. In these cases, empiric treatment can be an option prior to the application of assisted reproduction techniques. Empiric treatment can be categorized as hormonal, such as gonadotropins, antiestrogens and aromatase inhibitors, and antioxidant, with vitamins, trace elements and carnitine, among others. Although scientifically acceptable evidence is limited due to the absence of large randomized and controlled clinical trials, recent systematic reviews and meta-analyses show that treatment with gonadotropins, antiestrogens and antioxidants increases pregnancy and live birth rates and improves seminal parameters. Empiric medical treatment for idiopathic infertility can be considered in specific cases in order to improve semen quality and spontaneous fertility.
Topics: Algorithms; Asthenozoospermia; Humans; Male; Oligospermia
PubMed: 32284159
DOI: 10.1016/j.acuro.2019.10.007 -
EBioMedicine Oct 2023Asthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the...
BACKGROUND
Asthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the testes of humans and mice and encodes a type of adenosine kinase that is functionally involved in cellular nucleotide homeostasis and energy metabolism. We aimed to assess whether AK9 is involved in asthenozoospermia.
METHODS
One-hundred-and-sixty-five Chinese men with idiopathic asthenozoospermia were recruited. Whole-exome sequencing (WES) and Sanger sequencing were performed for genetic analyses. Papanicolaou staining, Haematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were used to observe the sperm morphology and structure. Ak9-knockout mice were generated using CRISPR-Cas9. Sperm adenosine was detected by liquid chromatography-mass spectrometry. Targeted sperm metabolomics was performed. Intracytoplasmic sperm injection (ICSI) was used to treat patients.
FINDINGS
We identified five patients harbouring bi-allelic AK9 mutations. Spermatozoa from men harbouring bi-allelic AK9 mutations have a decreased ability to sustain nucleotide homeostasis. Moreover, bi-allelic AK9 mutations inhibit glycolysis in sperm. Ak9-knockout male mice also presented similar phenotypes of asthenozoospermia. Interestingly, ICSI was effective in bi-allelic AK9 mutant patients in achieving good pregnancy outcomes.
INTERPRETATION
Defects in AK9 induce asthenozoospermia with defects in nucleotide homeostasis and energy metabolism. This sterile phenotype could be rescued by ICSI.
FUNDING
The National Natural Science Foundation of China (82071697), Medical Innovation Project of Fujian Province (2020-CXB-051), open project of the NHC Key Laboratory of Male Reproduction and Genetics in Guangzhou (KF202004), Medical Research Foundation of Guangdong Province (A2021269), Guangdong Provincial Reproductive Science Institute Innovation Team grants (C-03), and Outstanding Young Talents Program of Capital Medical University (B2205).
Topics: Humans; Pregnancy; Female; Male; Animals; Mice; Asthenozoospermia; Nucleotides; Semen; Spermatozoa; Infertility, Male
PubMed: 37713809
DOI: 10.1016/j.ebiom.2023.104798 -
Medicine Dec 2021Acupuncture is widely used for oligospermia and asthenozoospermia in China, but its effect is unclear. We aimed to determine the effectiveness and safety of acupuncture... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acupuncture is widely used for oligospermia and asthenozoospermia in China, but its effect is unclear. We aimed to determine the effectiveness and safety of acupuncture in treating oligospermia and asthenozoospermia.
METHODS
An electronic search for randomized controlled trials evaluating acupuncture treatment in patients with oligospermia and asthenozoospermia published from database inception to October 2018 was conducted in PubMed, EMBASE, the Chinese Biomedical Literature Database, the Chinese Scientific Journal Database (VIP Database), the Wan-Fang Database, the China National Knowledge Infrastructure and the Cochrane Library. We established search terms related to 3 areas (oligospermia, asthenozoospermia, and acupuncture). Two authors independently screened all identified citations and extracted the data. The methodological quality of the included trials was assessed using the Cochrane criteria.
RESULTS
Seven studies with a total of 527 subjects were screened according to inclusion and exclusion standards, and most of the studies had significant methodological weaknesses. Seven randomized controlled trials tested the effects of acupuncture compared with placebo acupuncture and conventional medications in patients with oligospermia and asthenozoospermia. The results of this study suggest that acupuncture alone has no clear superiority in improving sperm motility (standard mean difference [SMD] = 1.13, 95% confidence interval [CI]: -0.64 to 2.89), the sperm concentration (SMD = 0.32, 95% CI: 0.27-0.92) or semen volume compared with placebo acupuncture. No significant difference was found between acupuncture alone and conventional medications in improving sperm motility (SMD = -0.53, 95% CI: -2.54 to 1.48), the sperm concentration (SMD = -1.10, 95% CI: -1.48 to -0.72) or semen volume. However, adjuvant acupuncture may enhance the effect of medications on improving sperm motility (SMD = 4.10, 95% CI: 1.09-7.12) and the sperm concentration (SMD = 1.07, 95% CI: 0.739-1.40), but the study heterogeneity was too high to establish robust conclusions.
CONCLUSION
These results suggest that the current evidence does not support acupuncture as an effective treatment for oligospermia and asthenozoospermia; therefore, acupuncture is not currently recommended as a treatment for these conditions. However, owing to the high risk of bias among the included studies, the evidence is limited, and more large-scale, high-quality clinical trials are needed in the future.
TRIAL REGISTRATION NUMBER
PROSPERO CRD42018083885.
Topics: Acupuncture Therapy; Asthenozoospermia; Humans; Male; Oligospermia; Randomized Controlled Trials as Topic; Sperm Motility; Treatment Outcome
PubMed: 35049183
DOI: 10.1097/MD.0000000000027816 -
International Journal of Molecular... Mar 2021MicroRNAs applications were vastly studied throughout the years, spanning from potential cancer biomarkers to targeted therapies for various diseases. Out of these... (Review)
Review
MicroRNAs applications were vastly studied throughout the years, spanning from potential cancer biomarkers to targeted therapies for various diseases. Out of these utilizations, this paper focuses on their role in male infertility. Approximately 10-15% of worldwide couples are affected by infertility. Out of these, 50% are due to male determinants. The majority of cases still have an undetermined cause. Previous studies have found that the aberrant expression of microRNAs could be linked to certain reproductive dysfunctions in males. Further on, this study looked into the most recent literature published on this subject in order to assess the connection between the up-/down-regulation of various microRNAs and the roles they play in male infertility. MicroRNAs were found to be abundant and stable in the seminal liquid, which led to a facile identification using regular RNA detection methods. It was observed that the concentration of microRNAs in semen was modified in the case of patients suffering from asthenozoospermia and azoospermia. Moreover, idiopathic male infertility was associated with a single nucleotide polymorphism of the microRNA binding site. Future studies should focus their attention on discovering future treatments against male infertility targeting specific microRNAs and also on developing new and improved contraceptive methods.
Topics: Adult; Argonaute Proteins; Asthenozoospermia; Azoospermia; Binding Sites; Gene Expression Regulation; Humans; Infertility, Male; Male; MicroRNAs; Polymorphism, Single Nucleotide; RNA-Induced Silencing Complex; Semen; Spermatogenesis
PubMed: 33805594
DOI: 10.3390/ijms22062910 -
Andrologia Mar 2020Semen sample with poor sperm motility, which called asthenozoospermia, is considered as one of the main factors contributing to male infertility. Recognition of the... (Review)
Review
Semen sample with poor sperm motility, which called asthenozoospermia, is considered as one of the main factors contributing to male infertility. Recognition of the cellular and molecular pathways contributing to sperm motility reduction may lead to applying novel treatment strategies for overcoming low sperm motility in asthenozoospermia individuals. In this review, we intend to discuss the main causes of sperm motility reduction in asthenozoospermia and some treatment strategies used to overcome low sperm motility.
Topics: Antioxidants; Asthenozoospermia; Humans; Male; Sperm Motility
PubMed: 31680293
DOI: 10.1111/and.13463 -
Andrology Sep 2023Oligoasthenoteratozoospermia (OAT) is one of the most complex aggregators of male gametic problems. However, the genetic etiology of OAT is still largely unknown.
BACKGROUND
Oligoasthenoteratozoospermia (OAT) is one of the most complex aggregators of male gametic problems. However, the genetic etiology of OAT is still largely unknown.
OBJECTIVES
To reveal the new genetic factors responsible for male infertility owning to OAT and reveal the outcomes of the affected patients from intracytoplasmic sperm injection (ICSI).
MATERIALS AND METHODS
Two infertile men with typical OAT were recruited in 2018 and retrospected a cohort that included 47 patients with OAT from 2013 to 2021. Fifty healthy men with proven fertility served as control subjects. To identify the novel pathogenic variants, whole-exome sequencing and Sanger sequencing were used. In silico analysis revealed the affecting of the variants. Field emission scanning electron microscopy was employed to observe the morphological defects of the spermatozoa. Immunofluorescence was used to analyze the expression and localization of the related protein. CRISPR/Cas9 was used to generate the mouse model. ICSI was used as a treatment for the patients and to assess the effects of the pathogenic variant on fertilization and embryo development.
RESULTS
We identified a loss-of-function mutation NM_001170574.2:c.823G > T (p.Glu275*) in X-linked TENT5D from two patients with OAT. This variant is highly deleterious and has not been found in the human population. The count of patients' spermatozoa is dramatically decreased and displays multiple morphologic abnormalities with poor motility. Tent5d knockout mice are infertile and exhibit parallel defects. ICSI could rescue the infertility of the Tent5d knockout male mice. Moreover, the proband was treated with ICSI and achieved a successful pregnancy outcome for the first time. Subsequent mutation screening identified no TENT5D mutations among 47 additional patients with OAT and 50 control subjects.
CONCLUSION
Mutation in TENT5D results in OAT and male infertility, and this terrible situation could be rescued by ICSI.
Topics: Female; Animals; Mice; Humans; Male; Pregnancy; Infertility, Male; Oligospermia; Asthenozoospermia; Semen; Spermatozoa; Mutation
PubMed: 36746179
DOI: 10.1111/andr.13407