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1
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Tang P, Wang J, Tang X, Li Y, Li S. Insulin‑like growth factor 2 in spermatogenesis dysfunction (Review). Mol Med Rep 2025; 31:129. [PMID: 40116127 PMCID: PMC11938415 DOI: 10.3892/mmr.2025.13494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/21/2025] [Indexed: 03/23/2025] Open
Abstract
Spermatogenesis dysfunction is characterized by abnormal morphology, destruction, atrophy of seminiferous tubules, blocked differentiation of spermatogenic cells, decreased sperm count and increased sperm abnormalities. Inflammation, oxidative stress, endoplasmic reticulum stress and obesity are important factors leading to spermatogenesis dysfunction. It has been demonstrated that insulin‑like growth factor 2 (IGF2) is closely related to the aforementioned factors. In the present review, the relationship between IGF2 and inflammation, oxidative stress, ER stress and obesity was investigated, providing theoretical and experimental evidence on the role of IGF2 in the prevention and treatment of spermatogenesis dysfunction of male infertility.
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Affiliation(s)
- Pingping Tang
- Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jiale Wang
- Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaohan Tang
- Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yichun Li
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital University of South China, Hengyang, Hunan 421001, P.R. China
| | - Suyun Li
- Clinical Anatomy and Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
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2
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Qiu Y, Shimada K, Yamamoto K, Ikawa M. Loss of CCDC188 causes male infertility with defects in the sperm head-neck connection in mice†. Biol Reprod 2025; 112:169-178. [PMID: 39292630 PMCID: PMC11736427 DOI: 10.1093/biolre/ioae137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/08/2024] [Accepted: 09/17/2024] [Indexed: 09/20/2024] Open
Abstract
Acephalic spermatozoa syndrome represents a rare genetic and reproductive disease, which is defined as semen composed of mostly headless spermatozoa. The connecting piece in the neck region, also known as the head-to-tail coupling apparatus, plays a crucial role in the tight linkage between the sperm head and tail. Dysfunction of this structure can lead to separation of sperm heads and tails, and male infertility. Using the mouse as an experimental model, several proteins have been identified as associated with the head-to-tail coupling apparatus and disruption of these proteins causes acephalic spermatozoa. However, the molecular mechanism underlying this morphologic anomaly and head-to-tail coupling apparatus remains elusive. In this study, we focused on coiled-coil domain containing 188 (Ccdc188), which shows testis-enriched expression. To elucidate the physiological role of CCDC188, we generated a knockout mouse line using the CRISPR/Cas9 system. Ccdc188 knockout male mice were sterile, indicating that CCDC188 is indispensable for male fertility. Most Ccdc188-null spermatozoa were acephalic. Transmission electron microscopy revealed that while the sperm head-to-tail coupling apparatus could assemble properly without CCDC188, the head-to-tail coupling apparatus failed to attach to the nucleus during spermiogenesis, leading to sperm head and neck separation. In addition, we found almost all of the spermatozoa in the cauda epididymis lacked a mitochondrial sheath. Taken together, we demonstrated that CCDC188 plays a crucial role in forming a tight sperm head-neck junction.
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Affiliation(s)
- Yumiao Qiu
- Research Institute for Microbial Diseases, Osaka university, Osaka, 565-0871, Japan
- Graduate School of Medicine, Osaka university, Osaka, 565-0871, Japan
| | - Keisuke Shimada
- Research Institute for Microbial Diseases, Osaka university, Osaka, 565-0871, Japan
| | - Kaito Yamamoto
- Research Institute for Microbial Diseases, Osaka university, Osaka, 565-0871, Japan
| | - Masahito Ikawa
- Research Institute for Microbial Diseases, Osaka university, Osaka, 565-0871, Japan
- Graduate School of Medicine, Osaka university, Osaka, 565-0871, Japan
- The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Center for Infectious Disease Education and Research, Osaka university, Osaka 565-0871, Japan
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Xia H, Zhang J, Mao W, Yi K, Wang T, Liao L. Pathogenesis of acephalic spermatozoa syndrome caused by PMFBP1 mutation. Basic Clin Androl 2024; 34:22. [PMID: 39668357 PMCID: PMC11639112 DOI: 10.1186/s12610-024-00240-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 09/26/2024] [Indexed: 12/14/2024] Open
Abstract
BACKGROUND Acephalic spermatozoa syndrome is a rare but severe type of teratozoospermia. The familial trait of acephalic spermatozoa syndrome suggests that genetic factors play an important role. However, known mutations account for only some acephalic spermatozoa syndrome patients, and more studies are needed to elucidate its pathogenesis. The current study aimed to elucidate the pathogenesis of acephalic spermatozoa syndrome caused by PMFBP1 mutation. RESULTS We identified a homozygous splice site mutation (NM_031293.2, c.2089-1G > T) in PMFBP1 through Sanger sequencing. Western blotting and immunofluorescence analyses revealed that this splice site mutation resulted in the absence of PMFBP1 protein expression in the patient's sperm cells. We generated an in vitro model carrying the splice site mutation in PMFBP1 and confirmed, through RT‒PCR and Sanger sequencing, that it led to a deletion of 4 base pairs from exon 15. CONCLUSION A homozygous splice site mutation results in a deletion of 4 bp from exon 15 of PMFBP1, thereby affecting the expression of the PMFBP1 protein. The absence of PMFBP1 protein expression can lead to acephalic spermatozoa syndrome. This finding elucidates the underlying cause of acephalic spermatozoa syndrome associated with this specific mutation (NM_031293.2, c.2089-1G > T) in PMFBP1.
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Affiliation(s)
- Huaqiang Xia
- Reproductive Medicine Center, Zhuzhou Central Hospital, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 410120, China
| | - Juan Zhang
- Reproductive Medicine Center, Zhuzhou Central Hospital, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 410120, China
| | - Wuyuan Mao
- Reproductive Medicine Center, Zhuzhou Central Hospital, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 410120, China
| | - Kangle Yi
- Hunan Institute of Animal and Veterinary Science, Changsha, 41000, Hunan, China
| | - Teng Wang
- Reproductive Medicine Center, Zhuzhou Central Hospital, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 410120, China
| | - Lingyan Liao
- Pharmacy Department, Zhuzhou Central Hospital, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 410120, China.
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Arora M, Mehta P, Sethi S, Anifandis G, Samara M, Singh R. Genetic etiological spectrum of sperm morphological abnormalities. J Assist Reprod Genet 2024; 41:2877-2929. [PMID: 39417902 PMCID: PMC11621285 DOI: 10.1007/s10815-024-03274-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024] Open
Abstract
PURPOSE Male infertility manifests in the form of a reduction in sperm count, sperm motility, or the loss of fertilizing ability. While the loss of sperm production can have mixed reasons, sperm structural defects, cumulatively known as teratozoospermia, have predominantly genetic bases. The aim of the present review is to undertake a comprehensive analysis of the genetic mutations leading to sperm morphological deformities/teratozoospermia. METHODS We undertook literature review for genes involved in sperm morphological abnormalities. The genes were classified according to the type of sperm defects they cause and on the basis of the level of evidence determined by the number of human studies and the availability of a mouse knockout. RESULTS Mutations in the SUN5, CEP112, BRDT, DNAH6, PMFBP1, TSGA10, and SPATA20 genes result in acephalic sperm; mutations in the DPY19L2, SPATA16, PICK1, CCNB3, CHPT1, PIWIL4, and TDRD9 genes cause globozoospermia; mutations in the AURKC gene cause macrozoospermia; mutations in the WDR12 gene cause tapered sperm head; mutations in the RNF220 and ADCY10 genes result in small sperm head; mutations in the AMZ2 gene lead to vacuolated head formation; mutations in the CC2D1B and KIAA1210 genes lead to pyriform head formation; mutations in the SEPT14, ZPBP1, FBXO43, ZCWPW1, KATNAL2, PNLDC1, and CCIN genes cause amorphous head; mutations in the SEPT12, RBMX, and ACTL7A genes cause deformed acrosome formation; mutations in the DNAH1, DNAH2, DNAH6, DNAH17, FSIP2, CFAP43, AK7, CHAP251, CFAP65, ARMC2 and several other genes result in multiple morphological abnormalities of sperm flagella (MMAF). CONCLUSIONS Altogether, mutations in 31 genes have been reported to cause head defects and mutations in 62 genes are known to cause sperm tail defects.
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Affiliation(s)
- Manvi Arora
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
| | - Poonam Mehta
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Shruti Sethi
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - George Anifandis
- Department of Obstetrics and Gynaecology, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larisa, Greece
| | - Mary Samara
- Department of Obstetrics and Gynaecology, School of Health Sciences, Faculty of Medicine, University of Thessaly, Larisa, Greece
| | - Rajender Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
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Zhang Y, Liu G, Huang L, He X, Su Y, Nie X, Mao Z, Xing X. SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction. Mol Hum Reprod 2024; 30:gaae022. [PMID: 38870534 DOI: 10.1093/molehr/gaae022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 05/21/2024] [Indexed: 06/15/2024] Open
Abstract
Acephalic spermatozoa syndrome (ASS) is a severe teratospermia with decaudated, decapitated, and malformed sperm, resulting in male infertility. Nuclear envelope protein SUN5 localizes to the junction between the sperm head and tail. Mutations in the SUN5 gene have been identified most frequently (33-47%) in ASS cases, and its molecular mechanism of action is yet to be explored. In the present study, we generated Sun5 knockout mice, which presented the phenotype of ASS. Nuclear membrane protein LaminB1 and cytoskeletal GTPases Septin12 and Septin2 were identified as potential partners for interacting with SUN5 by immunoprecipitation-mass spectrometry in mouse testis. Further studies demonstrated that SUN5 connected the nucleus by interacting with LaminB1 and connected the proximal centriole by interacting with Septin12. The binding between SUN5 and Septin12 promoted their aggregation together in the sperm neck. The disruption of the LaminB1/SUN5/Septin12 complex by Sun5 deficiency caused separation of the Septin12-proximal centriole from the nucleus, leading to the breakage of the head-to-tail junction. Collectively, these data provide new insights into the pathogenesis of ASS caused by SUN5 deficiency.
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Affiliation(s)
- Yunfei Zhang
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Gang Liu
- Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, China
| | - Lihua Huang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiyi He
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yuyan Su
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xinmin Nie
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zenghui Mao
- Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, China
| | - Xiaowei Xing
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
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Graziani A, Rocca MS, Vinanzi C, Masi G, Grande G, De Toni L, Ferlin A. Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence. Genes (Basel) 2024; 15:600. [PMID: 38790229 PMCID: PMC11120687 DOI: 10.3390/genes15050600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/26/2024] [Accepted: 05/01/2024] [Indexed: 05/26/2024] Open
Abstract
Several genes are implicated in spermatogenesis and fertility regulation, and these genes are presently being analysed in clinical practice due to their involvement in male factor infertility (MFI). However, there are still few genetic analyses that are currently recommended for use in clinical practice. In this manuscript, we reviewed the genetic causes of qualitative sperm defects. We distinguished between alterations causing reduced sperm motility (asthenozoospermia) and alterations causing changes in the typical morphology of sperm (teratozoospermia). In detail, the genetic causes of reduced sperm motility may be found in the alteration of genes associated with sperm mitochondrial DNA, mitochondrial proteins, ion transport and channels, and flagellar proteins. On the other hand, the genetic causes of changes in typical sperm morphology are related to conditions with a strong genetic basis, such as macrozoospermia, globozoospermia, and acephalic spermatozoa syndrome. We tried to distinguish alterations approved for routine clinical application from those still unsupported by adequate clinical studies. The most important aspect of the study was related to the correct identification of subjects to be tested and the correct application of genetic tests based on clear clinical data. The correct application of available genetic tests in a scenario where reduced sperm motility and changes in sperm morphology have been observed enables the delivery of a defined diagnosis and plays an important role in clinical decision-making. Finally, clarifying the genetic causes of MFI might, in future, contribute to reducing the proportion of so-called idiopathic MFI, which might indeed be defined as a subtype of MFI whose cause has not yet been revealed.
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Affiliation(s)
- Andrea Graziani
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
| | - Maria Santa Rocca
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
| | - Cinzia Vinanzi
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
| | - Giulia Masi
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
| | - Giuseppe Grande
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
| | - Luca De Toni
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
| | - Alberto Ferlin
- Department of Medicine, University of Padova, 35128 Padova, Italy; (A.G.); (G.M.); (L.D.T.)
- Unit of Andrology and Reproductive Medicine, University Hospital of Padova, 35128 Padova, Italy; (M.S.R.); (C.V.); (G.G.)
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Koilpillai JN, Nunan E, Butler L, Pinaffi F, Butcher JT. Reversible Contraception in Males: An Obtainable Target? BIOLOGY 2024; 13:291. [PMID: 38785772 PMCID: PMC11117788 DOI: 10.3390/biology13050291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/27/2024] [Accepted: 04/13/2024] [Indexed: 05/25/2024]
Abstract
The last few decades have brought contraception to the forefront of research, with great strides made in effectively targeting and optimizing the physiology, pharmacology, and delivery processes that prevent pregnancy. However, these advances still predominantly target female contraceptives for the prevention of contraception, whereas targeting the male sex has lagged far behind. This has led to a marked deficiency in safe and effective male contraceptive agents, resulting in a heavy dependence on female contraceptives to prevent unwanted and unplanned pregnancies. Current research in the veterinary field and in rodents highlights several promising avenues whereby novel, safe, and effective male contraceptive alternatives are being developed-with an emphasis on reduced side effects and reversibility potential. This review aims to discuss current and novel male contraceptives (both human and veterinary formulations) while highlighting their efficacy, advantages, and disadvantages.
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Affiliation(s)
- Joanna Nandita Koilpillai
- Comparative Biomedical Sciences Graduate Program, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Emily Nunan
- Comparative Biomedical Sciences Graduate Program, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Landon Butler
- Department of Integrative Biology, Oklahoma State University, Stillwater, OK 74078, USA
| | - Fabio Pinaffi
- Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
| | - Joshua T. Butcher
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
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Khan K, Zhang X, Dil S, Khan I, Unar A, Ye J, Zeb A, Zubair M, Shah W, Zhang H, Khan MA, Wu L, Xu B, Ma H, Wen Z, Shi Q. A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family. Basic Clin Androl 2024; 34:4. [PMID: 38317066 PMCID: PMC10840149 DOI: 10.1186/s12610-024-00220-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 01/25/2024] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND Acephalic spermatozoa syndrome is a rare type of teratozoospermia causing male infertility due to detachment of the sperm head and flagellum, which precludes fertilization potential. Although loss-of-function variations in several genes, including TSGA10, have been associated with acephalic spermatozoa syndrome, the genetic cause of many cases remains unclear. RESULTS We recruited a Pakistani family with two infertile brothers who suffered from acephalic spermatozoa syndrome. Through whole-exome sequencing (WES) followed by Sanger sequencing, we identified a novel missense variant in TSGA10 (c.1112T > C, p. Leu371Pro), which recessively co-segregated with the acephalic spermatozoa syndrome within this family. Ultrastructural analyses of spermatozoa from the patient revealed that 98% of flagellar cross-sections displayed abnormal axonemal ultrastructure, in addition to the head-flagellum detachment. Real-time quantitative PCR analysis revealed almost no detectable TSAG10 mRNA and western blot analysis also failed to detect TSAG10 protein in patient's sperm samples while TSGA10 expression was clearly detected in control samples. Consistently, immunofluorescence analysis demonstrated the presence of TSGA10 signal in the midpiece of sperm from the control but a complete absence of TSGA10 signal in sperm from the patient. CONCLUSION Altogether, our study identifies a novel TSGA10 pathogenic variant as a cause of acephalic spermatozoa syndrome in this family and provides information regarding the clinical manifestations associated with TSGA10 variants in human.
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Affiliation(s)
- Khalid Khan
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Xiangjun Zhang
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Sobia Dil
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Ihsan Khan
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Ahsanullah Unar
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Jingwei Ye
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Aurang Zeb
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Muhammad Zubair
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Wasim Shah
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Huan Zhang
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Muzammil Ahmad Khan
- Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Khyber Pakhtunkhwa, Pakistan
| | - Limin Wu
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Bo Xu
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China
| | - Hui Ma
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China.
| | - Zina Wen
- Chengdu Xi'nan Gynecological Hospital, Chengdu, Sichuan, China.
| | - Qinghua Shi
- Division of Reproduction and Genetics, The First Affiliated Hospital of University of Science and Technology of China, Institute of Health and Medicine, Hefei Comprehensive National Science Center, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, 230027, China.
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Wang X, Jiang C, Dai S, Shen G, Yang Y, Shen Y. Identification of nonfunctional SPATA20 causing acephalic spermatozoa syndrome in humans. Clin Genet 2023; 103:310-319. [PMID: 36415156 DOI: 10.1111/cge.14268] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022]
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.
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Affiliation(s)
- Xiang Wang
- Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Chuan Jiang
- Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Siyu Dai
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Gan Shen
- Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yihong Yang
- Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ying Shen
- Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
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10
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Sudhakar DVS, Phanindranath R, Jaishankar S, Ramani A, Kalamkar KP, Kumar U, Pawar AD, Dada R, Singh R, Gupta NJ, Deenadayal M, Tolani AD, Sharma Y, Anand A, Gopalakrishnan J, Thangaraj K. Exome sequencing and functional analyses revealed CETN1 variants leads to impaired cell division and male fertility. Hum Mol Genet 2023; 32:533-542. [PMID: 36048845 DOI: 10.1093/hmg/ddac216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 02/07/2023] Open
Abstract
Human spermatogenesis requires an orchestrated expression of numerous genes in various germ cell subtypes. Therefore, the genetic landscape of male infertility is highly complex. Known genetic factors alone account for at least 15% of male infertility. However, ~40% of infertile men remain undiagnosed and are classified as idiopathic infertile men. We performed exome sequencing in 47 idiopathic infertile men (discovery cohort), followed by replication study (40 variants in 33 genes) in 844 infertile men and 709 controls using Sequenom MassARRAY® based genotyping. We report 17 variants in twelve genes that comprise both previously reported (DNAH8, DNAH17, FISP2 and SPEF2) and novel candidate genes (BRDT, CETN1, CATSPERD, GMCL1, SPATA6, TSSK4, TSKS and ZNF318) for male infertility. The latter have a strong biological nexus to human spermatogenesis and their respective mouse knockouts are concordant with human phenotypes. One candidate gene CETN1, identified in this study, was sequenced in another independent cohort of 840 infertile and 689 fertile men. Further, CETN1 variants were functionally characterized using biophysical and cell biology approaches. We demonstrate that CETN1 variant- p.Met72Thr leads to multipolar cells, fragmented nuclei during mitosis leading to cell death and show significantly perturbed ciliary disassembly dynamics. Whereas CETN1-5' UTR variant; rs367716858 leads to loss of a methylation site and increased reporter gene expression in vitro. We report a total of eight novel candidate genes identified by exome sequencing, which may have diagnostic relevance and can contribute to improved diagnostic workup and clinical management of male infertility.
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Affiliation(s)
| | - Regur Phanindranath
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India
| | - Shveta Jaishankar
- Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, India
| | - Anand Ramani
- Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Düsseldorf 40225, Germany
| | - Kaustubh P Kalamkar
- Institute for Neurophysiology, University of Cologne, Cologne D-50931, Germany
| | - Umesh Kumar
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India
| | - Asmita D Pawar
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India
| | - Rima Dada
- All India Institute of Medical Sciences, New Delhi, India
| | - Rajender Singh
- Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India
| | | | | | | | - Yogendra Sharma
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India.,Indian Institute of Science Education and Research (IISER) Berhampur, Odisha, India
| | - Anuranjan Anand
- Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, India
| | - Jay Gopalakrishnan
- Institute of Human Genetics, University Hospital Düsseldorf, Heinrich-Heine-Universität, Düsseldorf 40225, Germany
| | - Kumarasamy Thangaraj
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, 500007, India.,Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India
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11
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Genome-Wide Association Screening Determines Peripheral Players in Male Fertility Maintenance. Int J Mol Sci 2022; 24:ijms24010524. [PMID: 36613967 PMCID: PMC9820667 DOI: 10.3390/ijms24010524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/21/2022] [Accepted: 12/24/2022] [Indexed: 12/30/2022] Open
Abstract
Deciphering the functional relationships of genes resulting from genome-wide screens for polymorphisms that are associated with phenotypic variations can be challenging. However, given the common association with certain phenotypes, a functional link should exist. We have tested this prediction in newly sequenced exomes of altogether 100 men representing different states of fertility. Fertile subjects presented with normal semen parameters and had naturally fathered offspring. In contrast, infertile probands were involuntarily childless and had reduced sperm quantity and quality. Genome-wide association study (GWAS) linked twelve non-synonymous single-nucleotide polymorphisms (SNPs) to fertility variation between both cohorts. The SNPs localized to nine genes for which previous evidence is in line with a role in male fertility maintenance: ANAPC1, CES1, FAM131C, HLA-DRB1, KMT2C, NOMO1, SAA1, SRGAP2, and SUSD2. Most of the SNPs residing in these genes imply amino acid exchanges that should only moderately affect protein functionality. In addition, proteins encoded by genes from present GWAS occupied peripheral positions in a protein-protein interaction network, the backbone of which consisted of genes listed in the Online Mendelian Inheritance in Man (OMIM) database for their implication in male infertility. Suggestive of an indirect impact on male fertility, the genes focused were indeed linked to each other, albeit mediated by other interactants. Thus, the chances of identifying a central player in male infertility by GWAS could be limited in general. Furthermore, the SNPs determined and the genes containing these might prove to have potential as biomarkers in the diagnosis of male fertility.
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12
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Deng TQ, Xie YL, Pu JB, Xuan J, Li XM. Compound heterozygous mutations in PMFBP1 cause acephalic spermatozoa syndrome: A case report. World J Clin Cases 2022; 10:12761-12767. [PMID: 36579083 PMCID: PMC9791525 DOI: 10.12998/wjcc.v10.i34.12761] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/20/2022] [Accepted: 11/04/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Acephalic spermatozoa syndrome (ASS) is an extremely rare form of severe teratozoospermia, where in most of the sperm either appear to lack heads or have disconnected or poorly connected heads and tails.
CASE SUMMARY We reported the case of a male patient with secondary infertility whose sperm showed typical ASS upon morphological analysis. Whole-exome sequencing was performed on the patient’s peripheral blood, which revealed two heterozygous variants of the PMFBP1 gene: PMFBP1c.414+1G>T (p.?) and PMFBP1c.393del (p.C132Afs*3).
CONCLUSION It is speculated that the compound homozygous mutation of PMFBP1 may be the cause of ASS. We conducted a literature review in order to provide the basis for genetic counseling and clinical diagnosis of patients with ASS.
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Affiliation(s)
- Tian-Qin Deng
- Reproductive Medical Center, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518028, Guangdong Province, China
| | - Yu-Li Xie
- Newborn Screening Center, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518028, Guangdong Province, China
| | - Jiang-Bo Pu
- Reproductive Medical Center, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518028, Guangdong Province, China
| | - Jiang Xuan
- Reproductive Medical Center, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518028, Guangdong Province, China
| | - Xue-Mei Li
- Reproductive Medical Center, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518028, Guangdong Province, China
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13
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Nie H, Tang Y, Zhang X, Tan Y, Qin W. Novel mutations of PMFBP1 in a man with acephalic spermatozoa defects. Mol Genet Genomic Med 2022; 10:e2020. [PMID: 35860846 PMCID: PMC9482405 DOI: 10.1002/mgg3.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 12/23/2021] [Accepted: 07/08/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND Acephalic spermatozoa (AS) is a serious but rare reproductive genetic disorder that causes infertility in men. To date, only a few genes associated with AS defects have been identified, including the polyamine modulated factor 1 binding protein 1 (PMFBP1) gene. Consistent with this, PMFBP1 localizes to the head-neck connection, which bridges the implantation fossa and basal body. METHODS A male patient was diagnosed as having an AS defect. Blood samples from all family members and a sample of the patient's semen were collected to determine the genetic causes of his infertility. RESULTS Compound heterozygote mutation in the PMFBP1 gene, which is associated with AS defects in the present case: two loss-of-function mutations, with one a nonsense mutation c.361C > T p.Gln121Ter, and another a splice donor mutation c.414 + 1G > T. The current study, together with previous studies, suggests that the nonsense mutation is responsible for a truncated PMFBP1 protein during its formation; a splice donor mutation c.414 + 1G > T might lead to new open reading frames, from which the dysfunction of an abnormal PMFBP1 protein might be predicted. Additionally, the expression of outer dense fiber 1 (ODF1) and ODF2 proteins has been experimentally shown to be regulated by the truncated PMFBP1 protein. CONCLUSION We herein present a case with AS defects associated with heterozygote mutations of PMFBP1, which have been shown to be rare and pathogenic; the association with an AS defect is a monogenic disorder with a recessive inherited pattern in the patient's family.
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Affiliation(s)
- Hua Nie
- NHC Key Laboratory of Male Reproduction and GeneticsGuangzhouChina
- Central Laboratory of Guangdong Provincial Reproductive Science InstituteGuangzhouChina
- Central Laboratory of Guangdong Provincial Fertility HospitalGuangzhouChina
| | - Yunge Tang
- NHC Key Laboratory of Male Reproduction and GeneticsGuangzhouChina
- Central Laboratory of Guangdong Provincial Reproductive Science InstituteGuangzhouChina
- Central Laboratory of Guangdong Provincial Fertility HospitalGuangzhouChina
| | | | - Yuqiu Tan
- Zhanjiang Jiuhe HospitalZhanjiangChina
| | - Weibing Qin
- NHC Key Laboratory of Male Reproduction and GeneticsGuangzhouChina
- Central Laboratory of Guangdong Provincial Reproductive Science InstituteGuangzhouChina
- Central Laboratory of Guangdong Provincial Fertility HospitalGuangzhouChina
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14
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Ying LJ, Yu L, Yang T, Wu YB, Xu JY, Jia YL, Zheng Y, Li F. Semen parameters are seriously affected in acephalic spermatozoa syndrome. Basic Clin Androl 2022; 32:20. [PMID: 36028792 PMCID: PMC9413908 DOI: 10.1186/s12610-022-00170-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/19/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous studies have reported that some patients with headless spermatozoa have poor semen quality, but there has been no published systematic analysis of semen quality in patients with different proportions of headless spermatozoa in semen. We aimed to explore the association of acephalic spermatozoa syndrome and semen quality in men with distinct proportions of headless spermatozoa. MATERIAL AND METHODS Semen parameter values in patients for whom headless spermatozoa were found in the ejaculates was studied and compared to that of 413 age-matched prenatal examination patients. All semen samples were analyzed following the same methodology in a single laboratory. RESULTS All semen parameter values except semen volume were negatively (P < 0.05) correlated with the proportion of headless spermatozoa. The semen samples were divided into four groups on the basis of the proportion of headless spermatozoa (PHS) as follows: 0 < PHS ≤ 5% (n = 172, Group A1); 5 < PHS ≤ 10% (n = 76, Group A2); 10 < PHS ≤ 20% (n = 71, Group B); and PHS > 20% (n = 71, Group C). In Group A1, only one semen parameter value (progressive motility) was lower than those of the control group, but in Group A2, this increased to five (sperm vitality, normal sperm morphology, sperm motility, VCL (curvilinear velocity) and ALH (amplitude of lateral head displacement)). Worse still, all semen parameter values were significantly lower in Group B and Group C than in the control group (P < 0.05). CONCLUSIONS Semen samples containing headless spermatozoa tend to have lower quality than samples without headless spermatozoa. Increases in the proportion of headless spermatozoa in semen are associated with decreased semen quality. We suggest that headless spermatozoa should be seriously assessed and accurately counted in semen analysis, especially for ejaculate in which the proportion of headless spermatozoa exceeds 5%.
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Affiliation(s)
- Li-Juan Ying
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China
| | - Lin Yu
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China
| | - Tingting Yang
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China
| | - Ying-Bi Wu
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China
| | - Jin-Yan Xu
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China
| | - Ye-Lin Jia
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China
| | - Yan Zheng
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China
| | - Fuping Li
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 1416, Section 1, Chenglong Avenue, Sichuan, 610066, Chengdu, China.
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15
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Male contraceptive development: A medicinal chemistry perspective. Eur J Med Chem 2022; 243:114709. [DOI: 10.1016/j.ejmech.2022.114709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/20/2022] [Accepted: 08/21/2022] [Indexed: 11/21/2022]
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16
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Gupta N, Sarkar S, Mehta P, Sankhwar SN, Rajender S. Polymorphisms in the HSF2, LRRC6, MEIG1 and PTIP genes correlate with sperm motility in idiopathic infertility. Andrologia 2022; 54:e14517. [PMID: 35768906 DOI: 10.1111/and.14517] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/05/2022] [Accepted: 06/12/2022] [Indexed: 11/28/2022] Open
Abstract
The aim of this study was to investigate the association of 24 functionally important single nucleotide polymorphisms (SNPs) with male infertility. In this cross-sectional study, we genotyped 24 functionally important single nucleotide polymorphisms in 24 infertility candidate genes in 500 oligo-/astheno-/oligoastheno-/normo-zoospermic infertile men with idiopathic infertility. Sequenom iPlex gold assay was used for genotyping. Sperm count and motility were compared between prevalent genotypes at each test locus. We did not observe any significant difference in the average sperm count between the alternate genotypes for the loci in the KLK3, LRRC6, MEIG1, HSF2, ESR2 and PTIP genes. However, we observed a significant difference in sperm motility between the alternate genotypes for the loci in the LRRC6, MEIG1, HSF2 and PTIP genes. Polymorphisms in the LRRC6 (rs200321595), MEIG1 (rs150031795), HSF2 (rs143986686) and PTIP (rs61752013) genes show association with sperm motility.
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Affiliation(s)
- Nishi Gupta
- Division of Endocrinology, Central Drug Research Institute, Lucknow, India
| | - Saumya Sarkar
- Division of Endocrinology, Central Drug Research Institute, Lucknow, India
| | - Poonam Mehta
- Division of Endocrinology, Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | | | - Singh Rajender
- Division of Endocrinology, Central Drug Research Institute, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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17
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Rajput N, Gahlay GK. Identification and in silico Characterization of Deleterious Single Nucleotide Variations in Human ZP2 Gene. Front Cell Dev Biol 2021; 9:763166. [PMID: 34869353 PMCID: PMC8635754 DOI: 10.3389/fcell.2021.763166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022] Open
Abstract
ZP2, an important component of the zona matrix, surrounds mammalian oocytes and facilitates fertilization. Recently, some studies have documented the association of mutations in genes encoding the zona matrix with the infertile status of human females. Single nucleotide polymorphisms are the most common type of genetic variations observed in a population and as per the dbSNP database, around 5,152 SNPs are reported to exist in the human ZP2 (hZP2) gene. Although a wide range of computational tools are publicly available, yet no computational studies have been done to date to identify and analyze structural and functional effects of deleterious SNPs on hZP2. In this study, we conducted a comprehensive in silico analysis of all the SNPs found in hZP2. Six different computational tools including SIFT and PolyPhen-2 predicted 18 common nsSNPs as deleterious of which 12 were predicted to most likely affect the structure/functional properties. These were either present in the N-term region crucial for sperm-zona interaction or in the zona domain. 31 additional SNPs in both coding and non-coding regions were also identified. Interestingly, some of these SNPs have been found to be present in infertile females in some recent studies.
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Affiliation(s)
- Neha Rajput
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, INDIA
| | - Gagandeep Kaur Gahlay
- Department of Molecular Biology and Biochemistry, Guru Nanak Dev University, Amritsar, INDIA
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18
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Tapia Contreras C, Hoyer-Fender S. The Transformation of the Centrosome into the Basal Body: Similarities and Dissimilarities between Somatic and Male Germ Cells and Their Relevance for Male Fertility. Cells 2021; 10:2266. [PMID: 34571916 PMCID: PMC8471410 DOI: 10.3390/cells10092266] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022] Open
Abstract
The sperm flagellum is essential for the transport of the genetic material toward the oocyte and thus the transmission of the genetic information to the next generation. During the haploid phase of spermatogenesis, i.e., spermiogenesis, a morphological and molecular restructuring of the male germ cell, the round spermatid, takes place that includes the silencing and compaction of the nucleus, the formation of the acrosomal vesicle from the Golgi apparatus, the formation of the sperm tail, and, finally, the shedding of excessive cytoplasm. Sperm tail formation starts in the round spermatid stage when the pair of centrioles moves toward the posterior pole of the nucleus. The sperm tail, eventually, becomes located opposed to the acrosomal vesicle, which develops at the anterior pole of the nucleus. The centriole pair tightly attaches to the nucleus, forming a nuclear membrane indentation. An articular structure is formed around the centriole pair known as the connecting piece, situated in the neck region and linking the sperm head to the tail, also named the head-to-tail coupling apparatus or, in short, HTCA. Finally, the sperm tail grows out from the distal centriole that is now transformed into the basal body of the flagellum. However, a centriole pair is found in nearly all cells of the body. In somatic cells, it accumulates a large mass of proteins, the pericentriolar material (PCM), that together constitute the centrosome, which is the main microtubule-organizing center of the cell, essential not only for the structuring of the cytoskeleton and the overall cellular organization but also for mitotic spindle formation and chromosome segregation. However, in post-mitotic (G1 or G0) cells, the centrosome is transformed into the basal body. In this case, one of the centrioles, which is always the oldest or mother centriole, grows the axoneme of a cilium. Most cells of the body carry a single cilium known as the primary cilium that serves as an antenna sensing the cell's environment. Besides, specialized cells develop multiple motile cilia differing in substructure from the immotile primary cilia that are essential in moving fluids or cargos over the cellular surface. Impairment of cilia formation causes numerous severe syndromes that are collectively subsumed as ciliopathies. This comparative overview serves to illustrate the molecular mechanisms of basal body formation, their similarities, and dissimilarities, in somatic versus male germ cells, by discussing the involved proteins/genes and their expression, localization, and function. The review, thus, aimed to provide a deeper knowledge of the molecular players that is essential for the expansion of clinical diagnostics and treatment of male fertility disorders.
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Affiliation(s)
| | - Sigrid Hoyer-Fender
- Göttingen Center of Molecular Biosciences, Johann-Friedrich-Blumenbach Institute for Zoology and Anthropology-Developmental Biology, Faculty of Biology and Psychology, Georg-August University of Göttingen, 37077 Göttingen, Germany;
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19
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Sha Y, Liu W, Li L, Serafimovski M, Isachenko V, Li Y, Chen J, Zhao B, Wang Y, Wei X. Pathogenic Variants in ACTRT1 Cause Acephalic Spermatozoa Syndrome. Front Cell Dev Biol 2021; 9:676246. [PMID: 34422805 PMCID: PMC8377740 DOI: 10.3389/fcell.2021.676246] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 07/20/2021] [Indexed: 12/02/2022] Open
Abstract
Acephalic spermatozoa syndrome is a rare type of teratozoospermia, but its pathogenesis is largely unknown. Here, we performed whole-exome sequencing for 34 patients with acephalic spermatozoa syndrome and identified pathogenic variants in the X-linked gene, ACTRT1, in two patients. Sanger sequencing confirmed the pathogenic variants of ACTRT1 in the patients. Both pathogenic variants of ACTRT1 were highly conserved, and in silico analysis revealed that they were deleterious and rare. Actrt1-knockout mice exhibited a similar acephalic spermatozoa phenotype. Therefore, we speculated that mutations in ACTRT1 account for acephalic spermatozoa syndrome. Moreover, the patients in this study conceived their children through artificial insemination. This study provides further insights for clinicians and researchers regarding the genetic etiology and therapeutic strategies for acephalic spermatozoa patients with pathogenic variants in ACTRT1.
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Affiliation(s)
- Yanwei Sha
- Department of Andrology, United Diagnostic and Research Center for Clinical Genetics, School of Public Health & Women and Children's Hospital, Xiamen University, Xiamen, China
| | - Wensheng Liu
- Obstetrics and Gynecology Center, Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Research Group for Reproductive Medicine, Department of Obstetrics and Gynecology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Lin Li
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Mario Serafimovski
- Center for Physiology and Pathophysiology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Vladimir Isachenko
- Research Group for Reproductive Medicine, Department of Obstetrics and Gynecology, Medical Faculty, University of Cologne, Cologne, Germany
| | - Youzhu Li
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jing Chen
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Bangrong Zhao
- NHC Key Laboratory of Family Planning and Healthy/Key Laboratory of Reproductive Medicine of Hebei Provincial, Shijiazhuang, China
| | - Yifeng Wang
- Obstetrics and Gynecology Center, Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoli Wei
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
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20
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Xiang M, Wang Y, Xu W, Zheng N, Zhang J, Duan Z, Zha X, Shi X, Wang F, Cao Y, Zhu F. Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10. J Assist Reprod Genet 2021; 38:2791-2799. [PMID: 34409526 DOI: 10.1007/s10815-021-02295-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/03/2021] [Indexed: 11/27/2022] Open
Abstract
PURPOSE To identify the genetic causes for acephalic spermatozoa syndrome. METHODS Whole-exome sequencing was performed on the proband from a non-consanguineous to identify pathogenic mutations for acephalic spermatozoa syndrome. Quantitative real-time polymerase chain reaction and whole genome sequencing were subjected to detect deletion. The functional effect of the identified splicing mutation was investigated by minigene assay. Western blot and immunofluorescence were performed to detect the expression level and localization of mutant TSGA10 protein. RESULTS Here, we identified a novel heterozygous splicing mutation in TSGA10 (NM_025244: c.1108-1G > T), while we confirmed that there was a de novo large deletion in the proband. The splicing mutation led to the skipping of the exon15 of TSGA10, which resulted in a truncated protein (p. A370Efs*293). Therefore, we speculated that the splicing mutation might affect transcription and translation without the dosage compensation of a normal allele, which possesses a large deletion including intact TSGA10. Western blot and immunofluorescence demonstrated that the very low expression level of truncated TSGA10 protein led the proband to present the acephalic spermatozoa phenotype. CONCLUSION Our finding expands the spectrum of pathogenic TSGA10 mutations that are responsible for ASS and male infertility. It is also important to remind us of paying attention to the compound heterozygous deletion in patients from non-consanguineous families, so that we can provide more precise genetic counseling for patients.
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Affiliation(s)
- Mingfei Xiang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Yu Wang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Weilong Xu
- School of Life Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Na Zheng
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jingjing Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Zongliu Duan
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xiaomin Zha
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xuanming Shi
- Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Fengsong Wang
- School of Life Science, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China.
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Fuxi Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- NHC Key Laboratory of Study On Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei, 230032, Anhui, China.
- Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China.
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21
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Wu B, Gao H, Liu C, Li W. The coupling apparatus of the sperm head and tail†. Biol Reprod 2021; 102:988-998. [PMID: 31995163 DOI: 10.1093/biolre/ioaa016] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/05/2019] [Accepted: 01/26/2020] [Indexed: 12/23/2022] Open
Abstract
A strong sperm head-tail coupling apparatus (HTCA) is needed to ensure the integrity of spermatozoa during their fierce competition to fertilize the egg. A lot of HTCA-specific components have evolved to strengthen the attachment of the tail to the implantation fossa at the sperm head. Defects in HTCA formation lead to acephalic spermatozoa syndrome and pathologies of some male infertility. Recent studies have provided insights into the pathogenic molecular mechanisms of acephalic spermatozoa syndrome. Here, we summarize the proteins involved in sperm neck development and focus on their roles in the formation of HTCA. In addition, we discuss the fine structures of the sperm neck in different species from an evolutionary view, highlighting the potential conservative mechanism of HTCA formation.
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Affiliation(s)
- Bingbing Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hui Gao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Chao Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.,Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
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22
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Zhang Y, Liu C, Wu B, Li L, Li W, Yuan L. The missing linker between SUN5 and PMFBP1 in sperm head-tail coupling apparatus. Nat Commun 2021; 12:4926. [PMID: 34389728 PMCID: PMC8363609 DOI: 10.1038/s41467-021-25227-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
The sperm head-to-tail coupling apparatus (HTCA) ensures sperm head-tail integrity while defective HTCA causes acephalic spermatozoa, rendering males infertile. Here, we show that CENTLEIN is indispensable for HTCA integrity and function, and that inactivation of CENTLEIN in mice leads to sperm decapitation and male sterility. We demonstrate that CENTLEIN directly interacts with both SUN5 and PMFBP1, two proteins localized in the HTCA and related with acephalic spermatozoa syndrome. We find that the absence of Centlein sets SUN5 and PMFBP1 apart, the former close to the sperm head and the latter in the decapitated tail. We show that lack of Sun5 results in CENTLEIN and PMFBP1 left in the decapitated tail, while disruption of Pmfbp1 results in SUN5 and CENTLEIN left on the detached sperm head. These results demonstrate that CENTLEIN cooperating with SUN5 and PMFBP1 participates in the HTCA assembly and integration of sperm head to the tail, indicating that impairments of CENTLEIN might be associated with acephalic spermatozoa syndrome in humans.
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Affiliation(s)
- Ying Zhang
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Chao Liu
- Fertility Preservation Lab, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, P.R. China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, Beijing, P.R. China
| | - Bingbing Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, Beijing, P.R. China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Liansheng Li
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Wei Li
- Fertility Preservation Lab, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, P.R. China.
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, Beijing, P.R. China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, P.R. China.
| | - Li Yuan
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing, P.R. China.
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23
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Shen YR, Wang HY, Tsai YC, Kuo YC, Wu SR, Wang CY, Kuo PL. The SEPT12 complex is required for the establishment of a functional sperm head-tail junction. Mol Hum Reprod 2021; 26:402-412. [PMID: 32392324 DOI: 10.1093/molehr/gaaa031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 03/30/2020] [Indexed: 01/11/2023] Open
Abstract
The connecting pieces of the sperm neck link the flagellum and the sperm head, and they are important for initiating flagellar beating. The connecting pieces are important building blocks for the sperm neck; however, the mechanism of connecting piece assembly is poorly understood. In the present study, we explored the role of septins in sperm motility and found that Sept12D197N knock-in (KI) mice produce acephalic and immotile spermatozoa. Electron microscopy analysis showed defective connecting pieces in sperm from KI mice, indicating that SEPT12 is required for the establishment of connecting pieces. We also found that SEPT12 formed a complex with SEPT1, SEPT2, SEPT10 and SEPT11 at the sperm neck and that the D197N mutation disrupted the complex, suggesting that the SEPT12 complex is involved in the assembly of connecting pieces. Additionally, we found that SEPT12 interacted and colocalized with γ-tubulin in elongating spermatids, implying that SEPT12 and pericentriolar materials jointly contribute to the formation of connecting pieces. Collectively, our findings suggest that SEPT12 is required for the formation of striated columns, and the capitulum and for maintaining the stability of the sperm head-tail junction.
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Affiliation(s)
- Yi-Ru Shen
- Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Han-Yu Wang
- Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yung-Chieh Tsai
- Department of Obstetrics and Gynecology, Chi-Mei Medical Center, Tainan, Taiwan.,Department of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Sport Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Yung-Che Kuo
- Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,TMU Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shang-Rung Wu
- Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Yih Wang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pao-Lin Kuo
- Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Obstetrics and Gynecology, National Cheng-Kung University Hospital, Tainan, Taiwan
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24
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Zhang Y, Yang L, Huang L, Liu G, Nie X, Zhang X, Xing X. SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice. Front Cell Dev Biol 2021; 9:684826. [PMID: 34268309 PMCID: PMC8276135 DOI: 10.3389/fcell.2021.684826] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/11/2021] [Indexed: 12/24/2022] Open
Abstract
Acephalic spermatozoa syndrome is a rare genetic and reproductive disease. Recent studies have shown that approximately 33–47% of patients with acephalic spermatozoa syndrome have SUN5 mutations, but the molecular mechanism underlying this phenomenon has not been elucidated. In this study, we generated Sun5 knockout mice and found that the head-to-tail linkage was broken in Sun5–/– mice, which was similar to human acephalic spermatozoa syndrome. Furthermore, ultrastructural imaging revealed that the head-tail coupling apparatus (HTCA) and the centrosome were distant from the nucleus at steps 9–10 during spermatid elongation. With the manchette disappearing at steps 13–14, the head and the tail segregated. To explore the molecular mechanism underlying this process, bioinformatic analysis was performed and showed that Sun5 may interact with Nesprin3. Further coimmunoprecipitation (Co-IP) and immunofluorescence assays confirmed that Sun5 and Nesprin3 were indeed bona fide interaction partners that formed the linker of the nucleoskeleton and cytoskeleton (LINC) complex participating in the connection of the head and tail of spermatozoa. Nesprin3 was located posterior and anterior to the nucleus during spermiogenesis in wild-type mice, whereas it lost its localization at the implantation fossa of the posterior region in Sun5–/– mice. Without correct localization of Nesprin3 at the nuclear membrane, the centrosome, which is the originator of the flagellum, was distant from the nucleus, which led to the separation of the head and tail. In addition, isobaric tag for relative and absolute quantitation results showed that 47 proteins were upregulated, and 56 proteins were downregulated, in the testis in Sun5–/– mice, and the downregulation of spermatogenesis-related proteins (Odf1 and Odf2) may also contribute to the damage to the spermatozoa head-to-tail linkage. Our findings suggested that Sun5 is essential for the localization of Nesprin3 at the posterior nuclear membrane, which plays an essential role in the sperm head-tail connection.
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Affiliation(s)
- Yunfei Zhang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Linfei Yang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Lihua Huang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Gang Liu
- The Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, China
| | - Xinmin Nie
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xinxing Zhang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.,Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaowei Xing
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
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25
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Xiang M, Wang Y, Wang K, Kong S, Lu M, Zhang J, Duan Z, Zha X, Shi X, Wang F, Cao Y, Zhu F. Novel Mutation and Deletion in SUN5 Cause Male Infertility with Acephalic Spermatozoa Syndrome. Reprod Sci 2021; 29:646-651. [PMID: 34159570 DOI: 10.1007/s43032-021-00665-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/10/2021] [Indexed: 10/21/2022]
Abstract
Acephalic spermatozoa syndrome (ASS) is a severe form of teratozoospermia, previous studies have shown that SUN5 mutations are the major cause of acephalic spermatozoa syndrome. This study is to identify the pathogenic mutations in SUN5 leading to ASS. PCR and Sanger sequence were performed to define the breakpoints and mutations in SUN5. Whole genome sequencing (WGS) was performed to detect heterozygous deletion. Western blotting and immunofluorescence analysis detected the expression level and localization of SUN5. Furthermore, the pathogenicity of the mutant SUN5 was predicted in silico and was verified by the experiments in vitro. We identified one novel homozygous missense mutation (c.775G>A; p.G259S) and one compound heterozygous including one reported missense mutation (c.1043A>T; p.N348I) and a large deletion that contains partial EFCAB8 ( NM_001143967 .1) and BPIFB2 ( NM_025227 ) and complete SUN5 ( NM_080675 ), and one recurrent homozygous splice-site mutation (c.340G>A; p.G114R) in SUN5 in three patients with ASS. Our results showed that SUN5 could not be detected in the patients' spermatozoa and the exogenous expression level of the mutant protein was decreased in transfected HEK-293T cells. This study expands the mutational spectrum of SUN5. We recommended a clinical diagnostic strategy for SUN5 genomic deletion to screen heterozygous deletions and indicated that the diagnostic value of screening for SUN5 mutations and deletions in infertile men with ASS.
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Affiliation(s)
- Mingfei Xiang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Yu Wang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Ke Wang
- School of Life Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Shuai Kong
- School of Life Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Mengmeng Lu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jingjing Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Zongliu Duan
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xiaomin Zha
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China.,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China.,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xuanming Shi
- Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Fengsong Wang
- School of Life Science, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Yunxia Cao
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China. .,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China. .,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China. .,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Fuxi Zhu
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China. .,NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, 230032, Anhui, China. .,Key Laboratory of Population Health Across Life Cycle, Ministry of Education of the People's Republic of China, Anhui Medical University, Hefei, 230032, Anhui, China. .,Anhui Province Key Laboratory of Reproductive Health and Genetics, Anhui Medical University, Hefei, 230022, Anhui, China.
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26
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Liu G, Xing X, Zhang H, Zhu W, Lin G, Lu G, Li W. Patients with acephalic spermatozoa syndrome linked to novel TSGA10/PMFBP1 variants have favorable pregnancy outcomes from intracytoplasmic sperm injection. Clin Genet 2021; 100:334-339. [PMID: 34089195 DOI: 10.1111/cge.14007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/27/2021] [Accepted: 06/02/2021] [Indexed: 11/26/2022]
Abstract
Acephalic spermatozoa syndrome is a rare form of teratozoospermia characterized by headless spermatozoa. Previous studies have found that variants in SUN5, PMFBP1, TSGA10, BRDT, and SPATC1L are associated with this phenotype. Many researchers have suggested that variants in TSGA10 without a proximal centriole might influence early embryonic development. This retrospective cohort study included 12 infertile men with severe acephalic spermatozoa in China. We identified six heterozygous variants and four homozygous variants in TSGA10/PMFBP1 in seven patients by whole-exome sequencing (WES). Acephalic spermatozoa defects due to different genetic variations may affect only spermatozoa morphology but do not reduce the chances of fertilization, affect embryo quality at early stages or impair intracytoplasmic sperm injection (ICSI) outcomes. Patients with TSGA10/PMFBP1 variations were all expected to have good prognoses with ICSI.
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Affiliation(s)
- Gang Liu
- The Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, China
| | - Xiaowei Xing
- Center for Medical Experiments, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Huan Zhang
- Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.,Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, China
| | - Wenbing Zhu
- The Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, China
| | - Ge Lin
- The Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, China.,Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.,Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, China
| | - Guangxiu Lu
- The Institute of Reproduction and Stem Cell Engineering, Central South University, Changsha, China.,Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.,Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, China.,Scientific Research Department, Hunan Guangxiu Hi-tech Life Technology Co., Ltd, Changsha, China
| | - Weina Li
- Department of Andrology, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.,Clinical Research Center for Reproduction and Genetics in Hunan Province, Changsha, China.,Scientific Research Department, Hunan Guangxiu Hi-tech Life Technology Co., Ltd, Changsha, China
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27
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Kolmykov S, Vasiliev G, Osadchuk L, Kleschev M, Osadchuk A. Whole-Exome Sequencing Analysis of Human Semen Quality in Russian Multiethnic Population. Front Genet 2021; 12:662846. [PMID: 34178030 PMCID: PMC8232892 DOI: 10.3389/fgene.2021.662846] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/19/2021] [Indexed: 01/12/2023] Open
Abstract
The global trend toward the reduction of human spermatogenic function observed in many countries, including Russia, raised the problem of extensive screening and monitoring of male fertility and elucidation of its genetic and ethnic mechanisms. Recently, whole-exome sequencing (WES) was developed as a powerful tool for genetic analysis of complex traits. We present here the first Russian WES study for identification of new genes associated with semen quality. The experimental 3 × 2 design of the WES study was based on the analysis of 157 samples including three ethnic groups—Slavs (59), Buryats (n = 49), and Yakuts (n = 49), and two different semen quality groups—pathozoospermia (n = 95) and normospermia (n = 62). Additionally, our WES study group was negative for complete AZF microdeletions of the Y-chromosome. The normospermia group included men with normal sperm parameters in accordance with the WHO-recommended reference limit. The pathozoospermia group included men with impaired semen quality, namely, with any combined parameters of sperm concentration <15 × 106/ml, and/or progressive motility <32%, and/or normal morphology <4%. The WES was performed for all 157 samples. Subsequent calling and filtering of variants were carried out according to the GATK Best Practices recommendations. On the genotyping stage, the samples were combined into four cohorts: three sets corresponded to three ethnic groups, and the fourth set contained all the 157 whole-exome samples. Association of the obtained polymorphisms with semen quality parameters was investigated using the χ2 test. To prioritize the obtained variants associated with pathozoospermia, their effects were determined using Ensembl Variant Effect Predictor. Moreover, polymorphisms located in genes expressed in the testis were revealed based on the genomic annotation. As a result, the nine potential SNP markers rs6971091, rs557806, rs610308, rs556052, rs1289658, rs278981, rs1129172, rs12268007, and rs17228441 were selected for subsequent verification on our previously collected population sample (about 1,500 males). The selected variants located in seven genes FAM71F1, PPP1R15A, TRIM45, PRAME, RBM47, WDFY4, and FSIP2 that are expressed in the testis and play an important role in cell proliferation, meiosis, and apoptosis.
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Affiliation(s)
- Semyon Kolmykov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia.,Department of Computational Biology, Sirius University of Science and Technology, Sochi, Russia
| | - Gennady Vasiliev
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
| | - Ludmila Osadchuk
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
| | - Maxim Kleschev
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
| | - Alexander Osadchuk
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia
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Arafah K, Lopez F, Cazin C, Kherraf ZE, Tassistro V, Loundou A, Arnoult C, Thierry-Mieg N, Bulet P, Guichaoua MR, Ray PF. Defect in the nuclear pore membrane glycoprotein 210-like gene is associated with extreme uncondensed sperm nuclear chromatin and male infertility: a case report. Hum Reprod 2021; 36:693-701. [PMID: 33332558 DOI: 10.1093/humrep/deaa329] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 10/23/2020] [Indexed: 12/30/2022] Open
Abstract
After the two meiotic divisions, haploid round spermatids undergo dramatic changes to become mature spermatozoa. One of the main transformations consists of compacting the cell nucleus to confer the sperm its remarkable hydrodynamic property and to protect its DNA from the oxidative stress it will encounter during its reproductive journey. Here, we studied an infertile subject with low sperm count, poor motility and highly abnormal spermatozoa with strikingly large heads due to highly uncondensed nuclear sperm DNA. Whole-exome sequencing was performed on the subject's DNA to identify the genetic defect responsible for this severe sperm anomaly. Bioinformatics analysis of exome sequence data uncovered a homozygous loss of function variant, ENST00000368559.7:c.718-1G>A, altering a consensus splice site expected to prevent the synthesis of the nucleoporin 210 like (NUP210L) protein. High-resolution mass spectrometry of sperm protein extracts did not reveal any NUP210L peptide sequence in the patient's sperm, contrary to what was observed in control donors, thus confirming the absence of NUP210L in the patient's sperm. Interestingly, homozygous Nup210l knock-out mice have been shown to be infertile due to a reduced sperm count, a high proportion of round-headed sperm, other head and flagella defects and a poor motility. NUP210L is almost exclusively expressed in the testis and sequence analogy suggests that it encodes a nuclear pore membrane glycoprotein. The protein might be crucial to regulate nuclear trafficking during and/or before spermiogenesis, its absence potentially impeding adequate nuclear compaction by preventing the entry of histone variants/transition proteins/protamines into the nucleus and/or by preventing the adequate replacement of core histones. This work describes a new gene necessary for male fertility, potentially improving the efficiency of the genetic diagnosis of male infertility. The function of NUP210L still remains to be resolved and its future investigation will help to understand the complex mechanisms necessary for sperm compaction.
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Affiliation(s)
| | | | - Caroline Cazin
- Institute for Advanced Biosciences, CR Inserm U1209, CNRS UMR5309, University Grenoble Alpes, Team « Génétique, Épigénétique et Thérapies de l'infertilité », Grenoble, France.,CHU Grenoble Alpes, UM GI-DPI, Grenoble 38000, France
| | - Zine-Eddine Kherraf
- Institute for Advanced Biosciences, CR Inserm U1209, CNRS UMR5309, University Grenoble Alpes, Team « Génétique, Épigénétique et Thérapies de l'infertilité », Grenoble, France.,CHU Grenoble Alpes, UM GI-DPI, Grenoble 38000, France
| | - Virginie Tassistro
- Aix Marseille Université, Avignon Université, CNRS, IRD, IMBE, Marseille, France
| | - Anderson Loundou
- Department of Public Health, Faculty of Medicine, Methodological Assistance Unity for Clinical Research, Marseille, France
| | - Christophe Arnoult
- Institute for Advanced Biosciences, CR Inserm U1209, CNRS UMR5309, University Grenoble Alpes, Team « Génétique, Épigénétique et Thérapies de l'infertilité », Grenoble, France
| | | | - Philippe Bulet
- Plateforme BioPark d'Archamps, Archamps, France.,Institute for Advanced Biosciences, CR Inserm U1209, CNRS UMR5309, University Grenoble Alpes, Team « Immunologie Analytique des Pathologies Chroniques », Grenoble, France
| | | | - Pierre F Ray
- Institute for Advanced Biosciences, CR Inserm U1209, CNRS UMR5309, University Grenoble Alpes, Team « Génétique, Épigénétique et Thérapies de l'infertilité », Grenoble, France.,CHU Grenoble Alpes, UM GI-DPI, Grenoble 38000, France
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29
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Wu B, Yu X, Liu C, Wang L, Huang T, Lu G, Chen ZJ, Li W, Liu H. Essential Role of CFAP53 in Sperm Flagellum Biogenesis. Front Cell Dev Biol 2021; 9:676910. [PMID: 34124066 PMCID: PMC8195676 DOI: 10.3389/fcell.2021.676910] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 04/30/2021] [Indexed: 11/26/2022] Open
Abstract
The sperm flagellum is essential for male fertility. Despite vigorous research progress toward understanding the pathogenesis of flagellum-related diseases, much remains unknown about the mechanisms underlying the flagellum biogenesis itself. Here, we show that the cilia and flagella associated protein 53 (Cfap53) gene is predominantly expressed in testes, and it is essential for sperm flagellum biogenesis. The knockout of this gene resulted in complete infertility in male mice but not in the females. CFAP53 localized to the manchette and sperm tail during spermiogenesis, the knockout of this gene impaired flagellum biogenesis. Furthermore, we identified two manchette and sperm tail-associated proteins that interacted with CFAP53 during spermiogenesis. Together, our results suggest that CFAP53 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with multiple morphological abnormalities of the flagella (MMAF).
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Affiliation(s)
- Bingbing Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, Beijing, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Xiaochen Yu
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Key laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Chao Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, Beijing, China
| | - Lina Wang
- Department of Respiratory Medicine, National Clinical Research Center of Respiratory Diseases, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Tao Huang
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Key laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
| | - Gang Lu
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Key laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Zi-Jiang Chen
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Key laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, Beijing, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Hongbin Liu
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
- Key laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong University, Jinan, China
- Shandong Key Laboratory of Reproductive Medicine, Jinan, China
- Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, China
- National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, China
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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30
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Thirumalai A, Amory JK. Emerging approaches to male contraception. Fertil Steril 2021; 115:1369-1376. [PMID: 33931201 DOI: 10.1016/j.fertnstert.2021.03.047] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 03/29/2021] [Indexed: 01/12/2023]
Abstract
Despite significant interests in contraception by men, effective methods of male contraception are limited to vasectomy and condoms. Recently, there have been several promising advances in male contraceptive research. This review will update readers on recent research in both hormonal and nonhormonal approaches to male contraception. Hormonal approaches to male contraception have been stymied by adverse effects, formulations requiring injections or implants, a 5% to10% nonresponse rate, as well as poor understanding of user acceptability. In the last several years, research has focused on novel, orally bioavailable androgens such as dimethandrolone undecanoate and 11β-methyl-19-nor-testosterone. Additionally, combinations of a topical testosterone gel combined with a gel containing segesterone acetate, a potent progestin, have shown promise in clinical trials recently. Simultaneously, significant preclinical progress has been made in several approaches to nonhormonal male contraceptives, including compounds that inhibit sperm motility such as eppin, compounds that inhibit retinoic acid binding or biosynthesis, and reversible approaches to obstruction of the vas deferens. It is imperative for these areas of research to continue making strides so that there is a gamut of contraceptive options for couples to choose from. Some of these approaches will hopefully reach clinical utility soon, greatly improving contraceptive choice for couples.
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Affiliation(s)
- Arthi Thirumalai
- Center for Research in Reproduction and Contraception, Department of Medicine, University of Washington, Seattle, Washington
| | - John K Amory
- Center for Research in Reproduction and Contraception, Department of Medicine, University of Washington, Seattle, Washington.
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31
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Zhang D, Huang WJ, Chen GY, Dong LH, Tang Y, Zhang H, Li QQ, Mei XY, Wang ZH, Lan FH. Pathogenesis of acephalic spermatozoa syndrome caused by SUN5 variant. Mol Hum Reprod 2021; 27:6225007. [PMID: 33848337 DOI: 10.1093/molehr/gaab028] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/26/2021] [Indexed: 02/04/2023] Open
Abstract
Acephalic spermatozoa syndrome (ASS) is a rare teratozoospermia that leads to male infertility. Previous work suggested a genetic origin. Variants of Sad1 and UNC84 domain containing 5 (SUN5) are the main genetic cause of ASS; however, its pathogenesis remains unclear. Here, we performed whole-exome sequencing in 10 unrelated ASS and identified 2 homozygous variants, c.381delA[p.V128Sfs7*] and c.675C>A[p.Y225X], and 1 compound variant, c.88 C > T[p.R30X] and c.381 delA [p.V128Sfs7*], in SUN5 in 4 patients. The c.381delA variant had been identified as pathogenic in previous reports, while c.675C>A and c.88 C > T were two novel variants which could lead to a premature termination codon (PTC) and resulted in loss of SUN5, and may also be pathogenic. SUN5 mRNA and protein were present at very low levels in ASS patients with SUN5 nonsense mutation. Furthermore, the distribution of outer dense fiber protein 1 (ODF1) and Nesprin3 was altered in sperm of ASS patients with SUN5 variants. The co-immunoprecipitation analysis indicated that SUN5 and ODF1, SUN5 and Nesprin3, and ODF1 and Nesprin3 interacted with each other in transfected HEK293T cells. Thus, we propose that SUN5, Nesprin3, and ODF1 may form a 'triplet' structure through interactions at neck of sperm. When gene variants resulted in a loss of SUN5, the 'triplet' structure disappears and then the head-tail junction becomes fragile, leading to the occurrence of ASS.
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Affiliation(s)
- Duo Zhang
- Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China
| | - Wu-Jian Huang
- Center for Reproductive Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Center for Reproductive Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China
| | - Guo-Yong Chen
- Center for Reproductive Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Center for Reproductive Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China
| | - Li-Hong Dong
- The Department of Clinical Laboratory, Fuzong Clinical College of Fujian University, Fuzhou, China
| | - Ying Tang
- Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China
| | - Hui Zhang
- Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China
| | - Qing-Qin Li
- Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China
| | - Xiao-Yan Mei
- Center for Reproductive Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Center for Reproductive Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China
| | - Zhi-Hong Wang
- Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China
| | - Feng-Hua Lan
- Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China.,Laboratory of Basic Medicine, Fuzong Clinical College of Fujian Medical University, Fuzhou, China.,Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, China
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32
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Mazaheri Moghaddam M, Mazaheri Moghaddam M, Hamzeiy H, Baghbanzadeh A, Pashazadeh F, Sakhinia E. Genetic basis of acephalic spermatozoa syndrome, and intracytoplasmic sperm injection outcomes in infertile men: a systematic scoping review. J Assist Reprod Genet 2021; 38:573-586. [PMID: 33452591 PMCID: PMC7910383 DOI: 10.1007/s10815-020-02008-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/08/2020] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Acephalic spermatozoa syndrome (ASS) is known as a severe type of teratozoospermia, defined as semen composed of mostly headless spermatozoa that affect male fertility. In this regard, this systematic review aimed to discuss gene variants associated with acephalic spermatozoa phenotype as well as the clinical outcomes of intracytoplasmic sperm injection (ICSI) treatment for the acephalic spermatozoa-associated male infertility. METHODS A systematic search was performed on PubMed, Embase, Scopus, and Ovid databases until May 17, 2020. This systematic scoping review was reported in terms of the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement. RESULTS Twenty articles were included in this systematic review. Whole-exome and Sanger sequencing have helped in the identification of variants in SUN5, PMFBP1, BRDT, TSGA10, DNAH6, HOOK1, and CEP112 genes as possible causes of this phenotype in humans. The results of the ICSI are conflicting due to both positive and negative reports of ICSI outcomes. CONCLUSION ASS has a genetic origin, and several genetic alterations related to the pathogenesis of this anomaly have been recently identified. Notably, only SUN5 and PMFBP1 mutations are well-known to be implicated in ASS. Accordingly, more functional studies are needed to confirm the pathogenicity of other variants. ICSI could provide a promising treatment for acephalic spermatozoa-associated male infertility. Besides the importance of sperm head-tail junction integrity, some other factors, whether within the sperm cell or female factors, may be involved in the ICSI outcome.
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Affiliation(s)
- Marziyeh Mazaheri Moghaddam
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Madiheh Mazaheri Moghaddam
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
| | - Hamid Hamzeiy
- Tabriz Genetic Analysis Centre (TGAC), Tabriz University of Medical Sciences, Tabriz, Iran
- Genomize Inc., Istanbul, Turkey
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Pashazadeh
- Research Center for Evidence-Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ebrahim Sakhinia
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Tabriz Genetic Analysis Centre (TGAC), Tabriz University of Medical Sciences, Tabriz, Iran.
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33
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A novel homozygous missense mutation of PMFBP1 causes acephalic spermatozoa syndrome. J Assist Reprod Genet 2021; 38:949-955. [PMID: 33484382 DOI: 10.1007/s10815-021-02075-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/13/2021] [Indexed: 10/22/2022] Open
Abstract
PURPOSE To identify the pathogenic mutation in PMFBP1 leading to acephalic spermatozoa syndrome. METHODS Sanger sequencing was used to screen for mutations in the known pathogenic genes SUN5 and PMFBP1 in a patient with acephalic spermatozoa syndrome. Western blotting and immunofluorescence were used to detect the expression and localization of PMFBP1 in sperm. At the same time, a PMFBP1 mutant was constructed, and the expression level of PMFBP1 protein was further verified by in vitro experiments. RESULTS We identified a novel homozygous PMFBP1 missense mutation, c.301A>C (p.T101P), in an infertile male from a consanguineous family. Our results showed that the expression of PMFBP1 mutant protein was decreased obviously in sperm of the patient. CONCLUSION Our results showed that the novel homozygous missense mutation of PMFBP1 may be a cause of acephalic spermatozoa syndrome, which provided a basis for genetic counseling for the patient.
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34
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Xavier MJ, Salas-Huetos A, Oud MS, Aston KI, Veltman JA. Disease gene discovery in male infertility: past, present and future. Hum Genet 2021; 140:7-19. [PMID: 32638125 PMCID: PMC7864819 DOI: 10.1007/s00439-020-02202-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022]
Abstract
Identifying the genes causing male infertility is important to increase our biological understanding as well as the diagnostic yield and clinical relevance of genetic testing in this disorder. While significant progress has been made in some areas, mainly in our knowledge of the genes underlying rare qualitative sperm defects, the same cannot be said for the genetics of quantitative sperm defects. Technological advances and approaches in genomics are critical for the process of disease gene identification. In this review we highlight the impact of various technological developments on male infertility gene discovery as well as functional validation, going from the past to the present and the future. In particular, we draw attention to the use of unbiased genomics approaches, the development of increasingly relevant functional assays and the importance of large-scale international collaboration to advance disease gene identification in male infertility.
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Affiliation(s)
- M J Xavier
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK
| | - A Salas-Huetos
- Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah, Salt Lake City, USA
| | - M S Oud
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
| | - K I Aston
- Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah, Salt Lake City, USA.
| | - J A Veltman
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne, UK.
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35
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Beurois J, Cazin C, Kherraf ZE, Martinez G, Celse T, Touré A, Arnoult C, Ray PF, Coutton C. Genetics of teratozoospermia: Back to the head. Best Pract Res Clin Endocrinol Metab 2020; 34:101473. [PMID: 33183966 DOI: 10.1016/j.beem.2020.101473] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Spermatozoa are polarized cells with a head and a flagellum joined by the connecting piece. Head integrity is critical for normal sperm function, and head defects consistently lead to male infertility. Abnormalities of the sperm head are among the most severe and characteristic sperm defects. Patients presenting with a monomorphic head sperm defects such as globozoospermia or marcrozoospermia were analyzed permitting to identify several key genes for spermatogenesis such as AURKC and DPY19L2. The study of patients with other specific sperm head defects such as acephalic spermatozoa have also enabled the identification of new infertility genes such as SUN5. Here, we review the genetic causes leading to morphological defects of sperm head. Advances in the genetics of male infertility are necessary to improve the management of infertility and will pave the road towards future strategies of treatments, especially for patients with the most severe phenotype as sperm head defects.
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Affiliation(s)
- Julie Beurois
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France
| | - Caroline Cazin
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France
| | - Zine-Eddine Kherraf
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France
| | - Guillaume Martinez
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France; CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France
| | - Tristan Celse
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France; CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France
| | - Aminata Touré
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France
| | - Christophe Arnoult
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France
| | - Pierre F Ray
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France
| | - Charles Coutton
- Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, 38000, Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France; CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France.
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36
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Jiao SY, Yang YH, Chen SR. Molecular genetics of infertility: loss-of-function mutations in humans and corresponding knockout/mutated mice. Hum Reprod Update 2020; 27:154-189. [PMID: 33118031 DOI: 10.1093/humupd/dmaa034] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 07/15/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Infertility is a major issue in human reproductive health, affecting an estimated 15% of couples worldwide. Infertility can result from disorders of sex development (DSD) or from reproductive endocrine disorders (REDs) with onset in infancy, early childhood or adolescence. Male infertility, accounting for roughly half of all infertility cases, generally manifests as decreased sperm count (azoospermia or oligozoospermia), attenuated sperm motility (asthenozoospermia) or a higher proportion of morphologically abnormal sperm (teratozoospermia). Female infertility can be divided into several classical types, including, but not limited to, oocyte maturation arrest, premature ovarian insufficiency (POI), fertilization failure and early embryonic arrest. An estimated one half of infertility cases have a genetic component; however, most genetic causes of human infertility are currently uncharacterized. The advent of high-throughput sequencing technologies has greatly facilitated the identification of infertility-associated gene mutations in patients over the past 20 years. OBJECTIVE AND RATIONALE This review aims to conduct a narrative review of the genetic causes of human infertility. Loss-of-function mutation discoveries related to human infertility are summarized and further illustrated in tables. Corresponding knockout/mutated animal models of causative genes for infertility are also introduced. SEARCH METHODS A search of the PubMed database was performed to identify relevant studies published in English. The term 'mutation' was combined with a range of search terms related to the core focus of the review: infertility, DSD, REDs, azoospermia or oligozoospermia, asthenozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF), primary ciliary dyskinesia (PCD), acephalic spermatozoa syndrome (ASS), globozoospermia, teratozoospermia, acrosome, oocyte maturation arrest, POI, zona pellucida, fertilization defects and early embryonic arrest. OUTCOMES Our search generated ∼2000 records. Overall, 350 articles were included in the final review. For genetic investigation of human infertility, the traditional candidate gene approach is proceeding slowly, whereas high-throughput sequencing technologies in larger cohorts of individuals is identifying an increasing number of causative genes linked to human infertility. This review provides a wide panel of gene mutations in several typical forms of human infertility, including DSD, REDs, male infertility (oligozoospermia, MMAF, PCD, ASS and globozoospermia) and female infertility (oocyte maturation arrest, POI, fertilization failure and early embryonic arrest). The causative genes, their identified mutations, mutation rate, studied population and their corresponding knockout/mutated mice of non-obstructive azoospermia, MMAF, ASS, globozoospermia, oocyte maturation arrest, POI, fertilization failure and early embryonic arrest are further illustrated by tables. In this review, we suggest that (i) our current knowledge of infertility is largely obtained from knockout mouse models; (ii) larger cohorts of clinical cases with distinct clinical characteristics need to be recruited in future studies; (iii) the whole picture of genetic causes of human infertility relies on both the identification of more mutations for distinct types of infertility and the integration of known mutation information; (iv) knockout/mutated animal models are needed to show whether the phenotypes of genetically altered animals are consistent with findings in human infertile patients carrying a deleterious mutation of the homologous gene; and (v) the molecular mechanisms underlying human infertility caused by pathogenic mutations are largely unclear in most current studies. WILDER IMPLICATIONS It is important to use our current understanding to identify avenues and priorities for future research in the field of genetic causes of infertility as well as to apply mutation knowledge to risk prediction, genetic diagnosis and potential treatment for human infertility.
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Affiliation(s)
- Shi-Ya Jiao
- Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 100875 Beijing, China
| | - Yi-Hong Yang
- Reproduction Medical Center of West China Second University Hospital, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University, 610041 Chengdu, China
| | - Su-Ren Chen
- Education Key Laboratory of Cell Proliferation & Regulation Biology, College of Life Sciences, Beijing Normal University, 100875 Beijing, China
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Chen S, Wang G, Zheng X, Ge S, Dai Y, Ping P, Chen X, Liu G, Zhang J, Yang Y, Zhang X, Zhong A, Zhu Y, Chu Q, Huang Y, Zhang Y, Shen C, Yuan Y, Yuan Q, Pei X, Cheng CY, Sun F. Whole-exome sequencing of a large Chinese azoospermia and severe oligospermia cohort identifies novel infertility causative variants and genes. Hum Mol Genet 2020; 29:2451-2459. [PMID: 32469048 DOI: 10.1093/hmg/ddaa101] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 05/17/2020] [Accepted: 05/25/2020] [Indexed: 12/16/2022] Open
Abstract
Abstract
Rare coding variants have been proven to be one of the significant factors contributing to spermatogenic failure in patients with non-obstructive azoospermia (NOA) and severe oligospermia (SO). To delineate the molecular characteristics of idiopathic NOA and SO, we performed whole-exome sequencing of 314 unrelated patients of Chinese Han origin and verified our findings by comparing to 400 fertile controls. We detected six pathogenic/likely pathogenic variants and four variants of unknown significance, in genes known to cause NOA/SO, and 9 of which had not been earlier reported. Additionally, we identified 20 novel NOA candidate genes affecting 25 patients. Among them, five (BRDT, CHD5, MCM9, MLH3 and ZFX) were considered as strong candidates based on the evidence obtained from murine functional studies and human single-cell (sc)RNA-sequencing data. These genetic findings provide insight into the aetiology of human NOA/SO and pave the way for further functional analysis and molecular diagnosis of male infertility.
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Affiliation(s)
- Shitao Chen
- International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Guishuan Wang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, 226001, China
| | - Xiaoguo Zheng
- International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Shunna Ge
- International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Yubing Dai
- International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiaotong University, Shanghai, 200030, China
| | - Ping Ping
- Department of Urology, Shanghai Human Sperm Bank, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, China
| | - Xiangfeng Chen
- Department of Urology, Shanghai Human Sperm Bank, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, China
| | - Guihua Liu
- Department of Andrology, Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
| | - Jing Zhang
- Department of Andrology, Reproductive Medicine Research Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
| | - Yang Yang
- Department of Reproduction, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China
| | - Xinzong Zhang
- Key Laboratory of Male Reproduction and Genetics, National Health and Family Planning Commission, Family Planning Research Institute of Guangdong Province, Guangzhou, 510031, China
| | - An Zhong
- Key Laboratory of Male Reproduction and Genetics, National Health and Family Planning Commission, Family Planning Research Institute of Guangdong Province, Guangzhou, 510031, China
| | - Yongtong Zhu
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Qingjun Chu
- Department of Obstetrics and Gynecology, Reproductive Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yonghan Huang
- The First People's Hospital of Foshan, Sun Yat-sen University, Foshan, 528000, China
| | - Yong Zhang
- Center of Assisted Reproductive Medicine, The Sixth Medical Center of PLA General Hospital, Beijing, 100083, China
| | - Changli Shen
- Reproductive Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yiming Yuan
- Peking University First Hospital Andrology Center & Urology Department, Beijing, 100034, China
| | - Qilong Yuan
- Guangdong Province Hospital of Chinese Medicine, Guangzhou, 510140, China
| | - Xiuying Pei
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - C Yan Cheng
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, New York, 10065, USA
| | - Fei Sun
- International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory for Reproductive Medicine, School of Medicine, Shanghai Jiaotong University, Shanghai, 200030, China
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, 226001, China
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Ye Y, Wei X, Sha Y, Li N, Yan X, Cheng L, Qiao D, Zhou W, Wu R, Liu Q, Li Y. Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human. Mol Genet Genomic Med 2020; 8:e1284. [PMID: 32410354 PMCID: PMC7336754 DOI: 10.1002/mgg3.1284] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 03/31/2020] [Accepted: 04/01/2020] [Indexed: 12/17/2022] Open
Abstract
Background Acephalic spermatozoa is an extremely rare type of teratozoospermia that is associated with male infertility. Several genes have been reported to be relevant to acephalic spermatozoa. Thus, more genetic pathogenesis needs to be explored. Methods Whole‐exome sequencing was performed in a patient with acephalic spermatozoa. Then Sanger sequencing was used for validation in the patient and his family. The patient's spermatozoa sample was observed by papanicolaou staining and transmission electron microscopy. Western blot and immunofluorescence were performed to detect the level and localization of related proteins. Results A novel homozygous frameshift insertion mutation c.545dupT;p.Ala183Serfs*10 in exon 8 of TSGA10 (NM_001349012.1) was identified. Our results showed misarranged mitochondrial sheath and abnormal flagellum in the patient's spermatozoa. TSGA10 failed to be detected in the patient's spermatozoa. However, the expression of SUN5 and PMFBP1 remained unaffected. Conclusion These results suggest that the novel homozygous frameshift insertion mutation of TSGA10 is a cause of acephalic spermatozoa.
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Affiliation(s)
- Yuanyuan Ye
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Xiaoli Wei
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yanwei Sha
- Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Na Li
- Intensive Care Unit, Fujian Medical University Xiamen Humanity Hospital, Xiamen, China
| | - Xiaohong Yan
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Ling Cheng
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Duanrui Qiao
- Department of Gynecology, Second Hospital of Jilin University, Changchun, China
| | - Weidong Zhou
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Rongfeng Wu
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Qiaobin Liu
- Center for Reproductive Medicine, the 174th Hospital of People's Liberation Army, Xiamen, China
| | - Youzhu Li
- Reproductive Medicine Center, The First Affiliated Hospital of Xiamen University, Xiamen, China
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Li R, Fan H, Zhang Q, Yang X, Zhan P, Feng S. Pericentric inversion in chromosome 1 and male infertility. Open Med (Wars) 2020; 15:343-348. [PMID: 33335995 PMCID: PMC7712408 DOI: 10.1515/med-2020-0404] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/02/2020] [Accepted: 03/01/2020] [Indexed: 11/15/2022] Open
Abstract
Pericentric inversion in chromosome 1 was thought to cause male infertility through spermatogenic impairment, regardless of the breakpoint position. However, carriers of pericentric inversion in chromosome 1 have been reported with normal fertility and familial transmission. Here, we report two cases of pericentric inversion in chromosome 1. One case was detected in utero via amniocentesis, and the other case was detected after the wife of the carrier experienced two spontaneous abortions within 5 years of marriage. Here, the effect of the breakpoint position of the inversion in chromosome 1 on male infertility is examined and compared with the published cases. The association between the breakpoint of pericentric inversion in chromosome 1 and spermatogenesis is also discussed. Overall, the results suggest that the breakpoint position deserves attention from physicians in genetic counseling as inversion carriers can produce offspring.
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Affiliation(s)
- Ranwei Li
- Department of Urology, The Second Hospital of Jilin
University, Changchun, China
| | - Haitao Fan
- Department of Urology, The Second Hospital of Jilin
University, Changchun, China
| | - Qiushuang Zhang
- Department of Urology, The Second Hospital of Jilin
University, Changchun, China
| | - Xiao Yang
- Department of Urology, The Second Hospital of Jilin
University, Changchun, China
| | - Peng Zhan
- Department of Urology, The Second Hospital of Jilin
University, Changchun, China
| | - Shuqiang Feng
- Department of Urology, The Second Hospital of Jilin
University, Changchun, China
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Li L, Feng F, Zhao M, Li T, Yue W, Ma X, Wang B, Yin C. NOTCH2 variant D1853H is mutated in two non-syndromic premature ovarian insufficiency patients from a Chinese pedigree. J Ovarian Res 2020; 13:41. [PMID: 32312275 PMCID: PMC7171760 DOI: 10.1186/s13048-020-00645-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/03/2020] [Indexed: 11/24/2022] Open
Abstract
Background Premature ovarian insufficiency (POI) is a severe disorder of female infertility, characterized by 4–6 months of amenorrhea before the age of 40 years, with elevated follicle stimulating hormone (FSH) levels (> 25 IU/L). Although several genes have been reported to contribute to the genetic basis of POI, the molecular mechanism of POI remains unclear. Methods Whole-exome sequencing (WES) was performed. Sanger sequencing was carried out to validate the variant in the proband and her mother. In silico algorithms were used to analyze the mutational effect of the variant. Protein 3D structural modeling was used for predicting mutated protein structures. Vector construction and plasmids transfection were performed, and subsequently RNA-sequencing (RNA-seq) was carried out in each group to dissect the differentially expressed genes in wild-type (WT) and D1853H NOTCH2 mutant expressing groups. Gene Ontology analysis was also used to analyze the enriched biological processes or pathways among the differentially expressed genes. Results We report two non-syndromic POI patients from a Chinese pedigree. The FSH level of the proband (the daughter) was 46 IU/L at the age of 22. Her menarche was at the age of 12, but she was amenorrhea at the age of 20. By WES, a rare heterozygous variant (c.5557G > C;p.D1853H) in the NOTCH2 gene was identified. In silico analysis suggested that p.D1853H was a pathogenic allele. Protein 3D structural modeling suggested that D1853H may enhance or weaken the electrostatic surface potential. By molecular analysis, we found that cells expressing the D1853H NOTCH2 mutant had similar effect in activating the NOTCH signaling pathway downstream target genes. However, 106 protein-coding genes were differentially expressed between D1853H expressing cells and WT NOTCH2 expressing cells, and these genes were enriched for collagen degradation, NCAM1 interactions and HDACs deacetylate histones, revealing a unknown underlying mechanism of the pathology that leads to POI. Conclusions We conclude that the rare heterozygous variant in NOTCH2 may be associated with POI. This finding provides researchers and clinicians with a better understanding of the etiology, molecular mechanism and genetic consulting of POI.
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Affiliation(s)
- Lin Li
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang, Beijing, 100026, China
| | - Fan Feng
- Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Haidian, Beijing, 100084, China
| | - Minying Zhao
- Department of Reproductive Medicine, the First Hospital of Shijiazhuang, 36 Fanxi Road, Shijiazhuang, 050011, Hebei, China
| | - Tengyan Li
- Center for Genetics, National Research Institute for Family Planning, 12, Dahuisi Road, Haidian, Beijing, 100081, China
| | - Wentao Yue
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang, Beijing, 100026, China
| | - Xu Ma
- Center for Genetics, National Research Institute for Family Planning, 12, Dahuisi Road, Haidian, Beijing, 100081, China.
| | - Binbin Wang
- Center for Genetics, National Research Institute for Family Planning, 12, Dahuisi Road, Haidian, Beijing, 100081, China.
| | - Chenghong Yin
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang, Beijing, 100026, China.
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Galletta BJ, Ortega JM, Smith SL, Fagerstrom CJ, Fear JM, Mahadevaraju S, Oliver B, Rusan NM. Sperm Head-Tail Linkage Requires Restriction of Pericentriolar Material to the Proximal Centriole End. Dev Cell 2020; 53:86-101.e7. [PMID: 32169161 DOI: 10.1016/j.devcel.2020.02.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/22/2019] [Accepted: 02/07/2020] [Indexed: 01/27/2023]
Abstract
The centriole, or basal body, is the center of attachment between the sperm head and tail. While the distal end of the centriole templates the cilia, the proximal end associates with the nucleus. Using Drosophila, we identify a centriole-centric mechanism that ensures proper proximal end docking to the nucleus. This mechanism relies on the restriction of pericentrin-like protein (PLP) and the pericentriolar material (PCM) to the proximal end of the centriole. PLP is restricted proximally by limiting its mRNA and protein to the earliest stages of centriole elongation. Ectopic positioning of PLP to more distal portions of the centriole is sufficient to redistribute PCM and microtubules along the entire centriole length. This results in erroneous, lateral centriole docking to the nucleus, leading to spermatid decapitation as a result of a failure to form a stable head-tail linkage.
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Affiliation(s)
- Brian J Galletta
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Jacob M Ortega
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Samantha L Smith
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Carey J Fagerstrom
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Justin M Fear
- Developmental Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sharvani Mahadevaraju
- Developmental Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Brian Oliver
- Developmental Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nasser M Rusan
- Cell and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Amory JK. Development of Novel Male Contraceptives. Clin Transl Sci 2020; 13:228-237. [PMID: 31618525 PMCID: PMC7070810 DOI: 10.1111/cts.12708] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 09/03/2019] [Indexed: 12/16/2022] Open
Abstract
Unintended pregnancy is surprisingly common, accounting for 40-50% of pregnancies worldwide. Contraception is the most effective means of preventing unintended pregnancy. Seventy percent of all contraceptives are used by women; however, some women are unable to use contraceptives due to health conditions or side effects. Many men wish to take a more active role family planning, but currently have only two effective male contraceptive options, condoms and vasectomy. Therefore, work to develop novel male contraceptives analogous to popular female methods, such as daily pills or long-acting shots and implants, is underway. This paper will briefly discuss the pros and cons of condoms and vasectomies, and then review the research into novel methods of male contraception.
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Affiliation(s)
- John K. Amory
- Department of MedicineCenter for Research in Reproduction and ContraceptionUniversity of WashingtonSeattleWashingtonUSA
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Nie H, Tang Y, Qin W. Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6279795. [PMID: 32104701 PMCID: PMC7035536 DOI: 10.1155/2020/6279795] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 12/21/2019] [Accepted: 01/07/2020] [Indexed: 12/16/2022]
Abstract
This review analyses the genetic mechanisms of acephalic spermatozoa (AS) defects, which are associated with primary infertility in men. Several target genes of headless sperms have been identified but intracytoplasmic sperm injection (ICSI) outcomes are complex. Based on electron microscopic observations, broken points of the sperm neck are AS defects that are based on various genes that can be classified into three subtypes: HOOK1, SUN5, and PMFBP1 genes of subtype II; TSGA10 and BRDT genes of subgroup III, while the genetic mechanism(s) and aetiology of AS defects of subtype I have not been described and remain to be explored. Interestingly, all AS sperm of subtype II achieved better ICSI outcomes than other subtypes, resulting in clinical pregnancies and live births. For subtype III, the failure of clinical pregnancy can be explained by the defects of paternal centrioles that arrest embryonic development; for subtype I, this was due to a lack of a distal centriole. Consequently, the embryo quality and potential ICSI results of AS defects can be predicted by the subtypes of AS defects. However, this conclusion with regard to ICSI outcomes based on subtypes still needs further research, while the existence of quality of oocyte and implantation failure in women cannot be ignored.
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Affiliation(s)
- Hua Nie
- NHC Key Laboratory of Male Reproduction and Genetics, Guangzhou, China
- Department of Central Laboratory of Family Planning Research Institute of Guangdong Province of China, Guangzhou, China
- Department of Central Laboratory of Family Planning Special Hospital of Guangdong Province of China, Guangzhou, China
| | - Yunge Tang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangzhou, China
- Department of Central Laboratory of Family Planning Research Institute of Guangdong Province of China, Guangzhou, China
- Department of Central Laboratory of Family Planning Special Hospital of Guangdong Province of China, Guangzhou, China
| | - Weibing Qin
- NHC Key Laboratory of Male Reproduction and Genetics, Guangzhou, China
- Department of Central Laboratory of Family Planning Research Institute of Guangdong Province of China, Guangzhou, China
- Department of Central Laboratory of Family Planning Special Hospital of Guangdong Province of China, Guangzhou, China
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Sha Y, Wang X, Yuan J, Zhu X, Su Z, Zhang X, Xu X, Wei X. Loss-of-function mutations in centrosomal protein 112 is associated with human acephalic spermatozoa phenotype. Clin Genet 2019; 97:321-328. [PMID: 31654588 DOI: 10.1111/cge.13662] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 10/20/2019] [Accepted: 10/22/2019] [Indexed: 01/01/2023]
Abstract
Acephalic spermatozoa, characterized by the headless sperm in the ejaculate, is a rare type of teratozoospermia. Here, we recruited two infertile patients with an acephalic spermatozoa phenotype to investigate the genetic pathology of acephalic spermatozoa. Whole-exome sequencing analysis was performed and found mutations in CEP112 in the two patients: homozygous mutation c.496C > T:p.(Arg166X) in exon 5 from P1; and the biallelic mutations c.2074C > T:p.(Arg692Trp) in exon 20 and c.2104C > T:p.(Arg702Cys) in exon 20 from P2. Sanger sequencing confirmed the CEP112 mutations in the two patients. In silico analysis revealed that these CEP112 mutations are deleterious and rare, and all the mutations impact the coiled-coil domain of CEP112, which may affect the protein function. The c.496C > T:p.Arg166X resulted in a truncated CEP112, which was verified by the mutation expression plasmid. The CEP112 expression was significantly reduced in the P2, suggesting the biallelic mutations c.2074C > T and c.2104C > T may affect the function and stability of CEP112. Therefore, we speculate that the loss-of-function mutations in CEP112 may be account for the human acephalic spermatozoa phenotype.
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Affiliation(s)
- Yanwei Sha
- Department of Andrology, United Diagnostic and Research Center for Clinical Genetics, School of Public Health and Women and Children's Hospital, Xiamen University, Xiamen, Fujian, China
| | - Xiong Wang
- Reproductive Medicine Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - JinTing Yuan
- School of Environmental Science and Engineering, Tianjin University, Tianjin, China
| | - Xingshen Zhu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
| | - Zhiying Su
- Department of Andrology, United Diagnostic and Research Center for Clinical Genetics, School of Public Health and Women and Children's Hospital, Xiamen University, Xiamen, Fujian, China
| | - Xuequan Zhang
- Department of Andrology, Xiamen Children's Hospital, Xiamen, Fujian, China
| | - Xiaohui Xu
- Laboratory of genetics and cell biology, Medical college, Qingdao University, Qingdao, Shandong, China
| | - Xiaoli Wei
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
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Guerri G, Maniscalchi T, Barati S, Busetto GM, Del Giudice F, De Berardinis E, Cannarella R, Calogero AE, Bertelli M. Non-syndromic monogenic male infertility. ACTA BIO-MEDICA : ATENEI PARMENSIS 2019; 90:62-67. [PMID: 31577257 PMCID: PMC7233647 DOI: 10.23750/abm.v90i10-s.8762] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 08/06/2019] [Indexed: 11/23/2022]
Abstract
Infertility is a widespread clinical problem affecting 8-12% of couples worldwide. Of these, about 30% are diagnosed with idiopathic infertility since no causative factor is found. Overall 40-50% of cases are due to male reproductive defects. Numerical or structural chromosome abnormalities have long been associated with male infertility. Monogenic mutations have only recently been addressed in the pathogenesis of this condition. Mutations of specific genes involved in meiosis, mitosis or spermiohistogenesis result in spermatogenic failure, leading to the following anomalies: insufficient (oligozoospermia) or no (azoospermia) sperm production, limited progressive and/or total sperm motility (asthenozoospermia), altered sperm morphology (teratozoospermia), or combinations thereof. Androgen insensitivity, causing hormonal and sexual impairment in males with normal karyotype, also affects male fertility. The genetic causes of non-syndromic monogenic of male infertility are summarized in this article and a gene panel is proposed. (www.actabiomedica.it)
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Abstract
Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to male infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing. Genetic screening is relevant for its diagnostic value, clinical decision making, and appropriate genetic counselling. Anomalies in sex chromosomes have major roles in severe spermatogenic impairment. Autosome-linked gene mutations are mainly involved in central hypogonadism, monomorphic teratozoospermia or asthenozoospermia, congenital obstructive azoospermia, and familial cases of quantitative spermatogenic disturbances. Results from whole-genome association studies suggest a marginal role for common variants as causative factors; however, some of these variants can be important for pharmacogenetic purposes. Results of studies on copy number variations (CNVs) demonstrate a considerably higher CNV load in infertile patients than in normozoospermic men, whereas whole-exome analysis has proved to be a highly successful diagnostic tool in familial cases of male infertility. Despite such efforts, the aetiology of infertility remains unknown in about 40% of patients, and the discovery of novel genetic factors in idiopathic infertility is a major challenge for the field of androgenetics. Large, international, and consortium-based whole-exome and whole-genome studies are the most promising approach for the discovery of the missing genetic aetiology of idiopathic male infertility.
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Petrachkova T, Wortinger LA, Bard AJ, Singh J, Warga RM, Kane DA. Lack of Cyclin B1 in zebrafish causes lengthening of G2 and M phases. Dev Biol 2019; 451:167-179. [PMID: 30930047 DOI: 10.1016/j.ydbio.2019.03.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 03/20/2019] [Accepted: 03/22/2019] [Indexed: 12/23/2022]
Abstract
An essential part of the Mitosis Promoting Factor, Cyclin B1 is indispensable for cells to enter mitosis. We report here that the zebrafish early arrest mutant specter is a loss-of-function mutation in the сyclin B1 gene. cyclin B1 is maternally transcribed in zebrafish, and the zygotic phenotype is apparent by early segmentation. Lack of zygotic Cyclin B1 does not stop cells from dividing, rather it causes an abnormal and elongated progression through the G2 and M phases of the cell cycle. Many mutant cells show signs of chromosomal instability or enter apoptosis. Using CRISPR-mediated gene editing, we produced a more severe gain-of-function mutation confirming that specter is the result of nonfunctional Cyclin B1. Although also a recessive phenotype, this new mutation produces an alternative splice-form of cyclin B1 mRNA, whose product lacks several key components for Cyclin B1, but not the Cdk1-binding domain. This mutant form of Cyclin B1 completely prevents cell division. We conclude that, although Cyclin B1 is critical for cells to enter mitosis, another cell cycle protein may be cooperating with Cdk1 at the G2/M checkpoint to sustain a partly functional Mitosis Promoting Factor.
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Affiliation(s)
- Tetiana Petrachkova
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, USA.
| | - Laura A Wortinger
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, USA
| | - Amber J Bard
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, USA
| | - Jyotika Singh
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, USA
| | - Rachel M Warga
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, USA
| | - Donald A Kane
- Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, USA
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New insights into the genetics of spermatogenic failure: a review of the literature. Hum Genet 2019; 138:125-140. [PMID: 30656449 DOI: 10.1007/s00439-019-01974-1] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 01/09/2019] [Indexed: 12/23/2022]
Abstract
Genetic anomalies are known to affect about 15% of infertile patients with azoospermia or severe oligozoospermia. Despite a throughout diagnostic work-up, in up to the 72% of the male partners of infertile couples, no etiological factor can be found; hence, the cause of infertility remains unclear. Recently, several novel genetic causes of spermatogenic failure (SPGF) have been described. The aim of this review was to collect all the available evidence of SPGF genetics, matching data from in-vitro and animal models with those in human beings to provide a comprehensive and updated overview of the genes capable of affecting spermatogenesis. By reviewing the literature, we provided a list of 60 candidate genes for SPGF. Their investigation by Next Generation Sequencing in large cohorts of patients with apparently idiopathic infertility would provide new interesting data about their racial- and ethnic-related prevalence in infertile patients, likely raising the diagnostic yields. We propose a phenotype-based approach to identify the genes to look for.
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Sha YW, Wang X, Xu X, Ding L, Liu WS, Li P, Su ZY, Chen J, Mei LB, Zheng LK, Wang HL, Kong SB, You M, Wu JF. Biallelic mutations in PMFBP1 cause acephalic spermatozoa. Clin Genet 2018; 95:277-286. [PMID: 30298696 DOI: 10.1111/cge.13461] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 10/02/2018] [Accepted: 10/03/2018] [Indexed: 12/23/2022]
Abstract
The majority of men with defects in spermatogenesis remain undiagnosed. Acephalic spermatozoa is one of the diseases causing primary infertility. However, the causes underlying over half of affected cases remain unclear. Here, we report by whole-exome sequencing the identification of homozygous and compound heterozygous truncating mutations in PMFBP1 of two unrelated individuals with acephalic spermatozoa. PMFBP1 was highly and specifically expressed in human and mouse testis. Furthermore, immunofluorescence staining in sperm from a normal control showed that PMFBP1 localizes to the head-flagella junction region, and the absence of PMFBP1 was confirmed in patients harboring PMFBP1 mutations. In addition, we generated Pmfbp1 knock-out (KO) mice, which we found recapitulate the acephalic sperm phenotype. Label-free quantitative proteomic analysis of testicular sperm from Pmfbp1 KO and control mice showed 124 and 35 proteins, respectively, increased or decreased in sperm from KO mice compared to that found in control mice. Gene ontology analysis indicates that the biological process of Golgi vesicle transport was the most highly enriched in differentially expressed proteins, indicating process defects related to Golgi complex function may disturb formation of the head-neck junction. Collectively, our data indicate that PMFBP1 is necessary for sperm morphology in both humans and mice, and that biallelic truncating mutations in PMFBP1 cause acephalic spermatozoa.
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Affiliation(s)
- Yan-Wei Sha
- Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Xiong Wang
- Reproductive Medicine Center, Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Xiaohui Xu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Lu Ding
- Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Wen-Sheng Liu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Ping Li
- Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Zhi-Ying Su
- Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Jing Chen
- Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Li-Bin Mei
- Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Liang-Kai Zheng
- Department of Pathology, Xiamen Maternity and Child Care Hospital, Xiamen, China
| | - Hai-Long Wang
- School of Medicine, Xiamen University, Xiamen, China
| | | | - Min You
- School of Public Health, Xiamen University, Xiamen, China
| | - Jian-Feng Wu
- Laboratory Animal Center, Xiamen University, Xiamen, China
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Genetic evaluation of patients with non-syndromic male infertility. J Assist Reprod Genet 2018; 35:1939-1951. [PMID: 30259277 DOI: 10.1007/s10815-018-1301-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 08/28/2018] [Indexed: 02/06/2023] Open
Abstract
PURPOSE This review provides an update on the genetics of male infertility with emphasis on the current state of research, the genetic disorders that can lead to non-syndromic male infertility, and the genetic tests available for patients. METHODS A comprehensive review of the scientific literature referenced in PubMed was conducted using keywords related to male infertility and genetics. The search included articles with English abstracts appearing online after 2000. RESULTS Mutations in 31 distinct genes have been identified as a cause of non-syndromic human male infertility, and the number is increasing constantly. Screening gene panels by high-throughput sequencing can be offered to patients in order to identify genes involved in various forms of human non-syndromic infertility. We propose a workflow for genetic tests which takes into account semen alterations. CONCLUSIONS The identification and characterization of the genetic basis of male infertility have broad implications not only for understanding the cause of infertility but also in determining the prognosis, selection of treatment options, and management of couples. Genetic diagnosis is essential for the success of ART techniques and for preserving future fertility as well as the prognosis for testicular sperm extraction (TESE) and adopted therapeutics.
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