Russian Journal of Genetics, volume 60, issue 11, pages 1457-1472

Genetic Variants Causing Teratozoospermia in Humans

Publication typeJournal Article
Publication date2024-11-25
scimago Q4
wos Q4
SJR0.185
CiteScore1.0
Impact factor0.6
ISSN10227954, 16083369
Abstract
It is known that pathogenic variants in genes regulating spermiogenesis can lead to the manifestation of monomorphic teratozoospermia, characterized by the predominance of morphological abnormalities of a unique type (globozoospermia, macrozoospermia, acephalic spermatozoa, or multiple morphological abnormalities of the sperm flagella), as well as to polymorphic teratozoospermia, in which several types of sperm abnormalities are found in the ejaculate. The information obtained from systematization and organization of existing research data on pathogenic genetic variants associated with abnormal sperm morphology can be useful for understanding the molecular genetic mechanisms of teratozoospermia. Analysis of literary sources and data contained in the Malacards, OMIM, KEGG, CTD, DisGeNET databases resulted in the collection and systematization of the information about 109 human genes, the pathogenic variants in which were associated with certain types of teratozoospermia, in particular, globozoospermia, the syndrome of multiple morphological abnormalities of the sperm flagella, dysplasia of the fibrous sheath, acephalic spermatozoa syndrome, macrozoospermia, and polymorphic teratozoospermia. Moreover, each type of teratozoospermia was found to be caused by the disruption of specific biological processes, and pathogenic variants in genes involved in the regulation of cytoskeletal organization and functioning as well as intracellular transport, made the greatest contribution to the development of genetically determined teratozoospermia.
Shao Z., Zhu Y., Gu M., Guo S., Yu H., Li K., Tang D., Xu Y., Lv M.
Asian Journal of Andrology scimago Q2 wos Q1 Open Access
2023-08-11 citations by CoLab: 11 Abstract  
Variations in the dynein axonemal heavy chain gene, dynein axonemal heavy chain 6 (DNAH6), lead to multiple morphological abnormalities of the flagella. Recent studies have reported that these deficiencies may result in sperm head deformation. However, whether DNAH6 is also involved in human acrosome biogenesis remains unknown. The purpose of this study was to investigate DNAH6 gene variants and their potential functions in the formation of defective sperm heads and flagella. Whole-exome sequencing was performed on a cohort of 375 patients with asthenoteratozoospermia from the First Affiliated Hospital of Anhui Medical University (Hefei, China). Hematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were performed to analyze the sperm morphology and ultrastructure. Immunofluorescence staining and Western blot analysis were conducted to examine the effects of genetic variants. We identified three novel deleterious variants in DNAH6 among three unrelated families. The absence of inner dynein arms and radial spokes was observed in the sperm of patients with DNAH6 variants. Additionally, deficiencies in the acrosome, abnormal chromatin compaction, and vacuole-containing sperm heads were observed in these patients with DNAH6 variants. The decreased levels of the component proteins in these defective structures were further confirmed in sperm from patients with DNAH6 variants using Western blot. After intracytoplasmic sperm injection (ICSI) treatment, the partner of one patient with a DNAH6 variant achieved successful pregnancy. Overall, novel variants in DNAH6 genes that contribute to defects in the sperm head and flagella were identified, and the findings indicated ICSI as an effective clinical treatment for such patients.
Crafa A., Condorelli R.A., Vignera S.L., Calogero A.E., Cannarella R.
World Journal of Men?s Health scimago Q1 wos Q1 Open Access
2023-01-01 citations by CoLab: 10
Wang Y., Chen G., Tang Z., Mei X., Lin C., Kang J., Lian J., Lu J., Liu Y., Lan F., Huang W., Zhang D.
Molecular Human Reproduction scimago Q1 wos Q1
2023-05-15 citations by CoLab: 6 Abstract  
Abstract Fertilization failure is a significant manifestation of unexplained male infertility. Previous work has suggested a genetic origin. In this study, we report on a man with unexplained infertility from a large consanguineous marriage family. Whole-exome sequencing and Sanger sequencing identified a homozygous frameshift variation of the IQ motif containing N (IQCN; GenBank: NM_001145304.1; c.1061_1062delAT; p.Y354Sfs*13) in the proband and one of his two brothers, who also remained infertile. Analyses of spermatozoa by quantitative RT-PCR indicated that the level of IQCN mRNA was significantly reduced compared to fertile men and the protein could not be detected by western blotting and immunofluorescent staining in the proband. Immunofluorescent staining of spermatozoa from fertile men showed that IQCN was located in the acrosomal region and translocated to the equatorial segment after the acrosome reaction. The proband spermatozoa had abnormal morphology and function. Finally, the proband couple underwent IVF with donor sperm and a healthy baby was born. Furthermore, we developed an Iqcn-KO mouse model using the CRISPR/Cas9 technique. Sperm quality, except for sperm motility, and the fertility of male Iqcn−/− mice were consistent with those of the proband. In conclusion, the findings in humans and mice demonstrate that the homozygous frameshift variant of IQCN causes male infertility owing to autosomal-recessive fertilization failure.
Zhao S., Meng L., Du Z., Tan Y., He W., Wang X.
Asian Journal of Andrology scimago Q2 wos Q1 Open Access
2023-03-22 citations by CoLab: 5 Abstract  
Male infertility is a major reproductive disorder, which is clinically characterized by highly heterogeneous phenotypes of abnormal sperm count or quality. To date, five male patients with biallelic loss-of-function (LOF) variants of PARN-like ribonuclease domain-containing exonuclease 1 (PNLDC1) have been reported to experience infertility with nonobstructive azoospermia. The aim of this study was to identify the genetic cause of male infertility with oligo-astheno-teratozoospermia (OAT) in a patient from a Chinese Han family. Whole-exome and Sanger sequencing analyses identified a homozygous LOF variant (NM_173516.2, c.142C>T, p.Gln48Ter) in PNLDC1. Hematoxylin and eosin staining revealed that the spermatozoa of the patient with OAT had an irregular head phenotype, including microcephaly, head tapering, and globozoospermia. Consistently, peanut agglutinin staining of the spermatozoa revealed a complete or partial loss of the acrosome. Furthermore, the disomy rate of chromosomes in the patient’s spermatozoa was significantly increased compared with that of a fertile control sample. We reported an LOF variant of the PNLDC1 gene responsible for OAT.
Chang Y., Jiang X., Liu W., Zhang D., Yang S., Zhao D.
Zygote scimago Q4 wos Q4
2023-02-06 citations by CoLab: 3 Abstract  
Summary In recent years, the incidence of teratospermia has been increasing, and it has become a very important factor leading to male infertility. The research on the molecular mechanism of teratospermia is also progressing rapidly. This article briefly summarizes the clinical incidence of teratozoospermia, and makes a retrospective summary of related studies reported in recent years. Specifically discussing the relationship between gene status and spermatozoa, the review aims to provide the basis for the genetic diagnosis and gene therapy of teratozoospermia.
Liu Y., Li Y., Meng L., Li K., Gao Y., Lv M., Guo R., Xu Y., Zhou P., Wei Z., He X., Cao Y., Wu H., Tan Y., Hua R.
Human Molecular Genetics scimago Q1 wos Q2
2023-01-27 citations by CoLab: 9 Abstract  
Abstract Oligoasthenoteratozoospermia (OAT) can result in male infertility due to reduced sperm motility and abnormal spermatozoan morphology. The Tektins are a family of highly conserved filamentous proteins expressed in the axoneme and associated structures in many different metazoan species. Earlier studies on mice identified Tektin3 (Tekt3) as a testis-enriched gene, and knockout of Tekt3 resulted in asthenozoospermia in the mice. Here, whole exome sequencing of 100 males with asthenozoospermia from unrelated families was performed, followed by Sanger sequencing, leading to the identification of TEKT3 as a candidate gene in two of these patients and their associated family members. In total, three mutations in the TEKT3 gene were identified in both these patients, including one homozygous deletion–insertion mutation (c.543_547delinsTTGAT: p.Glu182*) and one compound heterozygous mutation (c.[548G > A]; [752A > C], p.[(Arg183Gln)]; [(Gln251Pro)]). Both of these mutations resulted in the complete loss of TEKT3 expression. The patients were both found to produce sperm that, although they showed no apparent defects in the flagellar structure, had reduced progressive motility. In contrast to mice, most sperm from these two patients exhibited acrosomal hypoplasia, although this did not prevent the use of the sperm for in vitro fertilization through an ICSI approach. TEKT3 was found to bind to other TEKT proteins, suggesting that these proteins form a complex within human spermatozoa. Overall, these results suggest that a loss of TEKT3 function can contribute to OAT incidence in humans. TEKT3 deficiencies can reduce sperm motility and contribute to severe acrosomal hypoplasia in spermatozoa, compromising their normal function.
Martinez G., Metzler‐Guillemain C., Cazin C., Kherraf Z., Paulmyer‐Lacroix O., Arnoult C., Ray P., Coutton C.
Clinical Genetics scimago Q1 wos Q2
2023-01-10 citations by CoLab: 3 Abstract  
The study identifies a novel biallelic pathogenic mutation in SPATA20 (c.1957+2T>A) in one infertile patient presenting with partial globozoospermia supporting its involvement in sperm head defects. The sperm phenotype described in our patient is however slightly different from the typical acephalic spermatozoa syndrome (ASS) previously reported. This data suggests a phenotypic heterogeneity associated with SPATA20 mutation and raises the hypothesis of a phenotypic continuum between partial or pseudo-globozoospermia and ASS. Last, our study confirmed that ICSI does not seem to be a valuable therapeutic option for patient with SPATA20 mutation. This article is protected by copyright. All rights reserved.
Zhou X., Xi Q., Jia W., Li Z., Liu Z., Luo G., Xing C., Zhang D., Hou M., Liu H., Yang X., Luo Y., Peng X., Wang G., Zou T., et. al.
Molecular Genetics and Genomics scimago Q2 wos Q3
2022-12-27 citations by CoLab: 9 Abstract  
Male infertility, a global public health problem, exhibits complex pathogenic causes and genetic factors deserve further discovery and study. We identified a novel homozygous missense mutation c.224A > C (p.D75A) in ACTL7A gene in two infertile brothers with teratozoospermia by whole-exome sequencing (WES). In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) showed fertilization failure of the two affected couples. The three-dimensional (3D) models showed that a small section of α‐helix transformed into random coil in the mutant ACTL7A protein and mutant amino acid lacked a hydrogen bond with Ser170 amino acid. Immunofluorescence revealed that ACTL7A protein was degraded in sperms of patients. Transmission electron microscopy (TEM) analysis of sperms from the infertile patients showed that the irregular perinuclear theca (PT) and acrosomal ultrastructural defects. Furthermore, ACTL7A mutation caused abnormal localization and reduced the expression of PLCZ1 in sperms of the patients, which may be the key reasons for the fertilization failure after ICSI. Our findings expand the spectrum of ACTL7A mutations and provide novel theoretical basis for genetic counseling.
Moreno R.D.
WIREs Mechanisms of Disease scimago Q1 wos Q2
2022-12-09 citations by CoLab: 5 Abstract  
The mammalian acrosome is a secretory vesicle attached to the sperm nucleus whose fusion with the overlying plasma membrane is required to achieve fertilization. Acrosome biogenesis starts during meiosis, but it lasts through the entire process of haploid cell differentiation (spermiogenesis). Acrosome biogenesis is a stepwise process that involves membrane traffic from the Golgi apparatus, but it also seems that the lysosome/endosome system participates in this process. Defective sperm head morphology is accompanied by defective acrosome shape and function, and patients with these characteristics are infertile or subfertile. The most extreme case of acrosome biogenesis failure is globozoospermia syndrome, which is primarily characterized by the presence of round-headed spermatozoa without acrosomes with cytoskeleton defects around the nucleus and infertility. Several genes participating in acrosome biogenesis have been uncovered using genetic deletions in mice, but only a few of them have been found to be deleted or modified in patients with globozoospermia. Understanding acrosome biogenesis is crucial to uncovering the molecular basis of male infertility and developing new diagnostic tools and assisted reproductive technologies that may help infertile patients through more effective treatment techniques. This article is categorized under: Reproductive System Diseases > Environmental Factors Infectious Diseases > Stem Cells and Development Reproductive System Diseases > Molecular and Cellular Physiology.
Wang X., Jiang C., Dai S., Shen G., Yang Y., Shen Y.
Clinical Genetics scimago Q1 wos Q2
2022-11-21 citations by CoLab: 13 Abstract  
Acephalic spermatozoa syndrome (ASS) is a rare and severe type of teratozoospermia characterized by the predominance of headless spermatozoa in the ejaculate. However, knowledge about the causative genes associated with ASS in humans is limited. Loss-of-function of SPATA20 has been suggested to result in the separation of the sperm head and flagellum in mice, whereas there have been no cases reporting SPATA20 variants leading to human male infertility. In this study, a nonsense mutation in SPATA20 (c.619C>T, p.Arg207*) was first identified in an ASS patient. Moreover, this variant contributed to the degradation of SPATA20 and was associated with decreased expression of SPATA6, which plays a vital role in the assembly of the sperm head-tail conjunction in humans. In addition, the infertility caused by loss-of-function mutation of SPATA20 might not be rescued by intracytoplasmic sperm injection (ICSI). Collectively, our findings suggested that SPATA20 might be required for sperm head-tail conjunction formation in humans, the nonfunction of which may lead to male infertility related to ASS. The discovery of the loss-of-function mutation in SPATA20 enriches the gene variant spectrum of human ASS, further contributing to improved diagnosis, genetic counseling and prognosis for male infertility. This article is protected by copyright. All rights reserved.
Wang J., Wang W., Shen L., Zheng A., Meng Q., Li H., Yang S.
Frontiers in Genetics scimago Q2 wos Q2 Open Access
2022-11-08 citations by CoLab: 23 PDF Abstract  
Sperm carries male genetic information, and flagella help move the sperm to reach oocytes. When the ultrastructure of the flagella is abnormal, the sperm is unable to reach the oocyte and achieve insemination. Multiple morphological abnormalities of sperm flagella (MMAF) is a relatively rare idiopathic condition that is mainly characterized by multiple defects in sperm flagella. In the last decade, with the development of high-throughput DNA sequencing approaches, many genes have been revealed to be related to MMAF. However, the differences in sperm phenotypes and reproductive outcomes in many cases are attributed to different pathogenic genes or different pathogenic mutations in the same gene. Here, we will review information about the various phenotypes resulting from different pathogenic genes, including sperm ultrastructure and encoding proteins with their location and functions as well as assisted reproductive technology (ART) outcomes. We will share our clinical detection and diagnosis experience to provide additional clinical views and broaden the understanding of this disease.
Davis A.P., Wiegers T.C., Johnson R.J., Sciaky D., Wiegers J., Mattingly C.
Nucleic Acids Research scimago Q1 wos Q1 Open Access
2022-09-28 citations by CoLab: 375 PDF Abstract  
Abstract The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) harmonizes cross-species heterogeneous data for chemical exposures and their biological repercussions by manually curating and interrelating chemical, gene, phenotype, anatomy, disease, taxa, and exposure content from the published literature. This curated information is integrated to generate inferences, providing potential molecular mediators to develop testable hypotheses and fill in knowledge gaps for environmental health. This dual nature, acting as both a knowledgebase and a discoverybase, makes CTD a unique resource for the scientific community. Here, we report a 20% increase in overall CTD content for 17 100 chemicals, 54 300 genes, 6100 phenotypes, 7270 diseases and 202 000 exposure statements. We also present CTD Tetramers, a novel tool that computationally generates four-unit information blocks connecting a chemical, gene, phenotype, and disease to construct potential molecular mechanistic pathways. Finally, we integrate terms for human biological media used in the CTD Exposure module to corresponding CTD Anatomy pages, allowing users to survey the chemical profiles for any tissue-of-interest and see how these environmental biomarkers are related to phenotypes for any anatomical site. These, and other webpage visual enhancements, continue to promote CTD as a practical, user-friendly, and innovative resource for finding information and generating testable hypotheses about environmental health.
Sáez-Espinosa P., Robles-Gómez L., Ortega-López L., Aizpurua J., Gómez-Torres M.J.
2022-02-02 citations by CoLab: 3 PDF Abstract  
Globozoospermia is a rare and severe type of teratozoospermia characterized by the presence of round-headed, acrosomeless spermatozoa with cytoskeleton defects. Current data support a negative relationship between globozoospermia and intracytoplasmic sperm injection (ICSI) outcomes, revealing the need to perform exhaustive studies on this type of sperm disorder. The aim of this study was to evaluate different structural, functional and molecular sperm biomarkers in total globozoospermia with proper embryo development after ICSI. The combination of field-emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) allowed us to identify and correlate eight morphological patterns with both types of microscopy. Additionally, results reported a high percentage of coiled forms, with cytoplasmic retentions around the head and midpiece. By fluorescent microscopy, we detected that most of the sperm showed tubulin in the terminal piece of the flagellum and less than 1% displayed tyrosine phosphorylation in the flagellum. Moreover, we did not detect chaperone Heat shock-related 70 kDa protein 2 (HSPA2) in 85% of the cells. Overall, these findings provide new insights into globozoospermia, which could have potential implications in improving sperm selection methods for assisted reproductive techniques.
Zhu F., Cao Y., Wang Y., Xiang M., Zheng N.
Asian Journal of Andrology scimago Q2 wos Q1 Open Access
2022-01-21 citations by CoLab: 12
Ray P., Kherraf Z., Cazin C., Lestrade F., Muronova J., Coutton C., Arnoult C., Thierry-Mieg N.
Asian Journal of Andrology scimago Q2 wos Q1 Open Access
2022-01-11 citations by CoLab: 8

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