Corrigendum to "Deficiency in AK9 causes asthenozoospermia and male infertility by destabilising sperm nucleotide homeostasis" [EBioMedicine 96(2023) 104798].
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ABSTRACT:
SUBMITTER: Sha Y
PROVIDER: S-EPMC10793085 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Corrigendum to "Deficiency in AK9 causes asthenozoospermia and male infertility by destabilising sperm nucleotide homeostasis" [EBioMedicine 96(2023) 104798].
Sha Yanwei Y Liu Wensheng W Li Shu S Osadchuk Ludmila V LV Chen Yongjie Y Nie Hua H Gao Shuai S Xie Linna L Qin Weibing W Zhou Huiliang H Li Lin L
EBioMedicine 20240103
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Project description:BackgroundAsthenozoospermia 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.MethodsOne-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.FindingsWe 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.InterpretationDefects in AK9 induce asthenozoospermia with defects in nucleotide homeostasis and energy metabolism. This sterile phenotype could be rescued by ICSI.FundingThe 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).
| S-EPMC10507140 | biostudies-literature
Project description:Asthenozoospermia is the most common clinical symptom of male infertility. Molecular markers associated with asthenozoospermia spermatozoa are scarcely identified. The objective of this study was to screen the differentially expressed genes (DEGs) in asthenozoospermia spermatozoa and assess the underlying bioinformatics roles in regulation of sperm quality.Based on gene expression omnibus (GEO) database, the GSE22331, GSE1133, and GSE4193 expression profile data were downloaded. The DEGs of asthenozoospermia spermatozoa were identified. Germ cell specific genes in DEGs were further screened. Then, gene ontology (GO) and over-representation analysis of DEGs were performed, followed by protein-protein interaction (PPI) network analysis. Expressions of selected genes of TEX11, ADAMTS5, ASRGL1, GMCL1, PGK2, KLHL10 in normozoospermia and asthenozoospermia spermatozoa were identified using real time Reverse Transcription-Polymerase Chain Reaction (RT-PCR).A total of 1323 DEGs were identified, including 1140 down-regulated genes. Twenty one and 96 down-regulated genes were especially expressed in spermatogonia and round spermatids, suggesting their testicular origins and influences on sperm quality. Bioinformatics analysis showed enriched functions of ubiquitin-like protein transferase or protein binding activities in down-regulated genes. Expressions of selected genes were validated by RT-PCR, which was consistent with bioinformatical results.The present study provided a novel insight into the understanding of sperm quality, and a potential method and dataset for the diagnosis and assessment of sperm quality in the event of male infertility.
| S-EPMC6310515 | biostudies-literature
Project description:Motile cilia and sperm flagella share an evolutionarily conserved axonemal structure. Their structural and/or functional defects are associated with primary ciliary dyskinesia (PCD), a genetic disease characterized by chronic respiratory-tract infections and in which most males are infertile due to asthenozoospermia. Among the well-characterized axonemal protein complexes, the outer dynein arms (ODAs), through ATPase activity of their heavy chains (HCs), play a major role for cilia and flagella beating. However, the contribution of the different HCs (γ-type: DNAH5 and DNAH8 and β-type: DNAH9, DNAH11, and DNAH17) in ODAs from both organelles is unknown. By analyzing five male individuals who consulted for isolated infertility and displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17. The isolated infertility phenotype prompted us to compare the protein composition of ODAs in the sperm and ciliary axonemes from control individuals. We show that DNAH17 and DNAH8, but not DNAH5, DNAH9, or DNAH11, colocalize with α-tubulin along the sperm axoneme, whereas the reverse picture is observed in respiratory cilia, thus explaining the phenotype restricted to sperm cells. We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells; these analyses indicated the absence of DNAH17 and DNAH8, whereas DNAH2 and DNALI, two inner dynein arm components, were present. Overall, this study demonstrates that mutations in DNAH17 are responsible for isolated male infertility and provides information regarding ODA composition in human spermatozoa.
| S-EPMC6612517 | biostudies-literature
Project description: Not available
| S-EPMC6948202 | biostudies-literature
Project description:Osmoregulation plays a vital role in sperm function, encompassing spermatogenesis, maturation, and fertilization. Aquaglyceroporins, a subclass of aquaporins (AQPs), facilitate the transport of water and glycerol across the sperm membrane, with glycerol serving as an important substrate for sperm bioenergetics. This study aimed to elucidate the significance of AQP-mediated glycerol permeability in sperm motility. The presence and localization of AQP3 and AQP7 in human sperm were assessed using immunofluorescence. Subsequently, the glycerol permeability of spermatozoa obtained from normozoospermic individuals (n = 30) was measured, using stopped-flow light scattering, after incubation with specific aquaporin inhibitors targeting AQP3 (DFP00173), AQP7 (Z433927330), or general aquaglyceroporin (phloretin). Sperm from asthenozoospermic men (n = 30) were utilized to evaluate the AQP7-mediated glycerol permeability, and to compare it with that of normozoospermic men. Furthermore, hypermotile capacitated sperm cells were examined, to determine the AQP7 expression and membrane glycerol permeability. AQP3 was predominantly observed in the tail region, while AQP7 was present in the head, midpiece, and tail of human sperm. Our findings indicate that AQP7 plays a key role in glycerol permeability, as the inhibition of AQP7 resulted in a 55% decrease in glycerol diffusion across the sperm membrane. Importantly, this glycerol permeability impairment was evident in spermatozoa from asthenozoospermic individuals, suggesting the dysregulation of AQP7-mediated glycerol transport, despite similar AQP7 levels. Conversely, the AQP7 expression increased in capacitated sperm, compared to non-capacitated sperm. Hence, AQP7-mediated permeability may serve as a valuable indicator of sperm motility, and be crucial in sperm function.
| S-EPMC10416866 | biostudies-literature
Project description:PurposeAsthenozoospermia is a common cause of human male infertility characterized by reduced sperm motility. The molecular mechanism that impairs sperm motility is not fully understood. This study proposed to identify novel biomarkers by focusing on sperm tail proteomic analysis of asthenozoospermic patients.MethodsSperm were isolated from normozoospermic and asthenozoospermic semen samples. Tail fractions were obtained by sonication followed by Percoll gradient. The proteins were extracted by solubilization and subjected to two-dimensional gel electrophoresis (2-DE); then, the spots were analyzed using Image Master 2D Platinum software. The significantly increased/decreased amounts of proteins in the two groups were exploited by matrix-assisted laser desorption-ionization time-of-flight/time-of-flight (MALDI-TOF-TOF) mass spectrometry.ResultsThree hundred ninety protein spots were detected in both groups. Twenty-one protein spots that had significantly altered amounts (p < 0.05) were excised and exploited using MALDI-TOF-TOF mass spectrometry. They led to the identification of the following 14 unique proteins: Tubulin beta 2B; glutathione S-transferase Mu 3; keratin, type II cytoskeletal 1; outer dense fiber protein 2; voltage-dependent anion-selective channel protein 2; A-kinase anchor protein 4; cytochrome c oxidase subunit 6B; sperm protein associated with the nucleus on the X chromosome B; phospholipid hydroperoxide glutathione peroxidase-mitochondrial; isoaspartyl peptidase/L-asparaginase; heat shock-related 70 kDa protein 2; stress-70 protein, mitochondrial; glyceraldehyde-3-phosphate dehydrogenase, testis-specific and clusterin.ConclusionFourteen proteins present in different amounts in asthenozoospermic sperm tail samples were identified, four of which are reported here for the first time. These proteins might be used as markers for the better diagnosis of sperm dysfunctions, targets for male contraceptive development, and to predict embryo quality.
| S-EPMC4491089 | biostudies-literature
Project description:Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive disease manifested with recurrent infections of respiratory tract and infertility. DNAAF3 is identified as a novel gene associated with PCD and different mutations in DNAAF3 results in different clinical features of PCD patients, such as situs inversus, sinusitis and bronchiectasis. However, the sperm phenotypic characteristics of PCD males are generally poorly investigated. Our reproductive medicine centre received a case of PCD patient with infertility, who presented with sinusitis, recurrent infections of the lower airway and severe asthenozoospermia; However, no situs inversus was found in the patient. A novel homozygous mutation in DNAAF3(c.551T>A; p.V184E) was identified in the PCD patient by whole-exome sequencing. Subsequent Sanger sequencing further confirmed that the DNAAF3 had a homozygous missense variant in the fifth exon. Transmission electron microscopy and immunostaining analysis of the sperms from the patient showed a complete absence of outer dynein arms and partial absence of inner dynein arms, which resulted in the reduction in sperm motility. However, this infertility was overcome by intracytoplasmic sperm injections, as his wife achieved successful pregnancy. These findings showed that the PCD-associated pathogenic mutation within DNAAF3 also causes severe asthenozoospermia and male infertility ultimately due to sperm flagella axoneme defect in humans. Our study not only contributes to understand the sperm phenotypic characteristics of patients with DNAAF3 mutations but also expands the spectrum of DNAAF3 mutations and may contribute to the genetic diagnosis and therapy for infertile patient with PCD.
| S-EPMC10568663 | biostudies-literature
Project description:PurposeMale infertility is a complex multifactorial pathological condition, and asthenozoospermia (AZS) is one of the most common causes. Current evidence suggests the underlying role of the circadian clock on male fertility. This study aims to evaluate the expression levels of five principal clock genes in the sperm and their correlations with the sperm parameters in male infertility.MethodsWe determined the expression profiles of BMAL1, CLOCK, CRY1, PER1, and PER2 in the sperm of infertile men with AZS (n=38) and healthy fertile men (n=40) using quantitative real-time PCR. Then we performed comprehensive association analyses on the clock gene levels and the sperm parameters, including progressive and total motility, concentration, and normal morphology of the sperm.ResultsOur results showed that the expression levels of five clock genes (BMAL1, CLOCK, CRY1, PER1, and PER2) are significantly decreased in the sperm of the infertile men with AZS as compared with that of healthy fertile men (P< 0.01). All five clock gene levels are associated with the percentage of progressive/total sperm motility (r= 0.546/0.589~0.677/0.695, P< 0.01). We also discovered that a combination of BMAL1, CLOCK, CRY1, PER1, and PER2 could reach a high diagnostic performance (areas under the curves, 92%) for infertility with AZS.ConclusionsThis study first reports that sperm BMAL1, CLOCK, CRY1, PER1, and PER2 levels are altered in AZS and may be molecular markers for male infertility with AZS. These findings indicate the possibility of stabilizing circadian rhythmicity through therapeutic intervention on clock genes to prevent and treat infertility.
| S-EPMC8866580 | biostudies-literature
Project description:Male infertility is a worldwide medical problem. Asthenozoospermia is a common cause of infertility. Epigenetic modifications of DNA and histones have been shown to influence human infertility, but no research has explored whether N(6)-methyladenosine (m(6)A) level in RNA is associated with asthenozoospermia. Here, we collected a total of 52 semen samples, including 20 asthenozoospermia patients and 32 healthy controls. An LC-ESI-MS/MS method was used to detect m(6)A contents in sperm RNA, and real-time PCR was performed to determine the mRNA expression of demethylase (FTO, ALKBH5), methyltransferase (METTL3, METTL14, WTAP) and an m(6)A-selective-binding protein (YTHDF2). We found that m(6)A content (p = 0.033) and the mRNA expression of METTL3 (p = 0.016) and METTL14 (p = 0.025) in asthenozoospermia patients were significantly higher than those of controls. Increased m(6)A content was a risk factor for asthenozoospermia (odds ratio (OR) 3.229, 95% confidence interval (CI) 1.178 - 8.853, p = 0.023). Moreover, m(6)A content was correlated with the expression of METTL3 (r = 0.303, p = 0.032) and with sperm motility (progressive motility: r = -0.288, p = 0.038; non-progressive motility: r = -0.293, p = 0.037; immotility: r = 0.387, p = 0.005). Our data suggest that increased m(6)A content is a risk factor for asthenozoospermia and affects sperm motility. Methyltransferases, particularly METTL3, play key roles in increasing m(6)A contents in sperm RNA.
| S-EPMC4829835 | biostudies-literature
Project description:In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on morphological abnormalities of the sperm flagellum (MMAF), a phenotype also termed "short tails," which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole-exome sequencing of a cohort of 167 MMAF-affected individuals, we identified bi-allelic loss-of-function mutations in more than 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a tetratricopeptide repeat-containing protein related to the intraflagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant, and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss-of-function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF.
| S-EPMC6904810 | biostudies-literature