Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence
Abstract
:1. Male Factor Infertility and Semen Examination
2. Sperm Motility and Genetics of Reduced Sperm Motility
2.1. Sperm Motility
2.2. Sperm Mitochondrial DNA Content and Proteins
2.3. Ion Channels
2.4. Proteins of the Flagellum
2.4.1. MMAF
2.4.2. PCD
2.4.3. DFS
2.4.4. Other Genes
3. Sperm Morphology and Genetics of Reduced Sperm Typical Form
3.1. Sperm Morphology
3.2. Teratozoospermia
3.2.1. Macrozoospermia
3.2.2. Globoozoospermia
3.2.3. Acephalic Spermatozoa
3.2.4. Other Forms of Reduced Typical Sperm Morphology
4. Final Considerations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Sharma, A.; Minhas, S.; Dhillo, W.S.; Jayasena, C.N. Male Infertility Due to Testicular Disorders. J. Clin. Endocrinol. Metab. 2021, 106, e442–e459. [Google Scholar] [CrossRef] [PubMed]
- Ferlin, A.; Calogero, A.E.; Krausz, C.; Lombardo, F.; Paoli, D.; Rago, R.; Scarica, C.; Simoni, M.; Foresta, C.; Rochira, V.; et al. Management of Male Factor Infertility: Position Statement from the Italian Society of Andrology and Sexual Medicine (SIAMS). J. Endocrinol. Investig. 2022, 45, 1085–1113. [Google Scholar] [CrossRef] [PubMed]
- Fainberg, J.; Kashanian, J.A. Recent Advances in Understanding and Managing Male Infertility. F1000Research 2019, 8, 670. [Google Scholar] [CrossRef] [PubMed]
- Graziani, A.; Merico, M.; Grande, G.; Di Mambro, A.; Vinanzi, C.; Rocca, M.S.; Selice, R.; Ferlin, A. A Cryptozoospermic Infertile Male with Y Chromosome AZFc Microdeletion and Low FSH Levels Due to a Simultaneous Polymorphism in the FSHB Gene: A Case Report. Hum. Reprod. 2024, 39, 504–508. [Google Scholar] [CrossRef] [PubMed]
- Ferlin, A.; Dipresa, S.; Delbarba, A.; Maffezzoni, F.; Porcelli, T.; Cappelli, C.; Foresta, C. Contemporary Genetics-Based Diagnostics of Male Infertility. Expert Rev. Mol. Diagn. 2019, 19, 623–633. [Google Scholar] [CrossRef] [PubMed]
- Grande, G.; Graziani, A.; Ferlin, A. Guideline for Unexplained Couple Infertility: Misunderstandings on the Approach to the Male Factor. Hum. Reprod. 2024, 39, 859–860. [Google Scholar] [CrossRef] [PubMed]
- World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen; World Health Organization: Geneva, Switzerland, 2021; Volume 6. [Google Scholar]
- Björndahl, L.; Esteves, S.C.; Ferlin, A.; Jørgensen, N.; O’Flaherty, C. Improving Standard Practices in Studies Using Results from Basic Human Semen Examination. Andrology 2023, 11, 1225–1231. [Google Scholar] [CrossRef] [PubMed]
- Pereira, R.; Sousa, M. Morphological and Molecular Bases of Male Infertility: A Closer Look at Sperm Flagellum. Genes 2023, 14, 383. [Google Scholar] [CrossRef] [PubMed]
- Touré, A.; Martinez, G.; Kherraf, Z.E.; Cazin, C.; Beurois, J.; Arnoult, C.; Ray, P.F.; Coutton, C. The Genetic Architecture of Morphological Abnormalities of the Sperm Tail. Hum. Genet. 2021, 140, 21–42. [Google Scholar] [CrossRef] [PubMed]
- Kumar, N.; Singh, A.K. The Anatomy, Movement, and Functions of Human Sperm Tail: An Evolving Mystery. Biol. Reprod. 2021, 104, 508–520. [Google Scholar] [CrossRef] [PubMed]
- Kinukawa, M.; Ohmuro, J.; Baba, S.A.; Murashige, S.; Okuno, M.; Nagata, M.; Aoki, F. Analysis of Flagellar Bending in Hamster Spermatozoa: Characterization of an Effective Stroke. Biol. Reprod. 2005, 73, 1269–1274. [Google Scholar] [CrossRef] [PubMed]
- Ferlin, A.; Garolla, A.; Ghezzi, M.; Selice, R.; Palego, P.; Caretta, N.; Di Mambro, A.; Valente, U.; De Rocco Ponce, M.; Dipresa, S.; et al. Sperm Count and Hypogonadism as Markers of General Male Health. Eur. Urol. Focus 2021, 7, 205–213. [Google Scholar] [CrossRef]
- Gray, M.W. Mitochondrial Evolution. Cold Spring Harb. Perspect. Biol. 2012, 4, a011403. [Google Scholar] [CrossRef] [PubMed]
- Lynch, M.; Marinov, G.K. Membranes, Energetics, and Evolution across the Prokaryote-Eukaryote Divide. Elife 2017, 6, e20437. [Google Scholar] [CrossRef]
- Akbari, M.; Nilsen, H.L.; Montaldo, N. Pietro Dynamic Features of Human Mitochondrial DNA Maintenance and Transcription. Front. Cell Dev. Biol. 2022, 10, 984245. [Google Scholar] [CrossRef] [PubMed]
- Glancy, B.; Kim, Y.; Katti, P.; Willingham, T.B. The Functional Impact of Mitochondrial Structure Across Subcellular Scales. Front. Physiol. 2020, 11, 541040. [Google Scholar] [CrossRef] [PubMed]
- Moyes, C.D.; Battersby, B.J.; Leary, S.C. Regulation of Muscle Mitochondrial Design. J. Exp. Biol. 1998, 201, 299–307. [Google Scholar] [CrossRef] [PubMed]
- Ankel-Simons, F.; Cummins, J.M. Misconceptions about Mitochondria and Mammalian Fertilization: Implications for Theories on Human Evolution. Proc. Natl. Acad. Sci. USA 1996, 93, 13859–13863. [Google Scholar] [CrossRef]
- Hirata, S.; Hoshi, K.; Shoda, T.; Mabuchi, T. Spermatozoon and Mitochondrial DNA. Reprod. Med. Biol. 2002, 1, 41–47. [Google Scholar] [CrossRef] [PubMed]
- Piomboni, P.; Focarelli, R.; Stendardi, A.; Ferramosca, A.; Zara, V. The Role of Mitochondria in Energy Production for Human Sperm Motility. Int. J. Androl. 2012, 35, 109–124. [Google Scholar] [CrossRef] [PubMed]
- Ruiz-Pesini, E.; Diez, C.; Lapena, A.C.; Perez-Martos, A.; Montoya, J.; Alvarez, E.; Arenas, J.; Lopez-Perez, M.J. Correlation of Sperm Motility with Mitochondrial Enzymatic Activities. Clin. Chem. 1998, 44, 1616–1620. [Google Scholar] [CrossRef] [PubMed]
- Ruiz-Pesini, E.; Lapeña, A.C.; Díez-Sánchez, C.; Pérez-Martos, A.; Montoya, J.; Alvarez, E.; Díaz, M.; Urriés, A.; Montoro, L.; López-Pérez, M.J.; et al. Human MtDNA Haplogroups Associated with High or Reduced Spermatozoa Motility. Am. J. Hum. Genet. 2000, 67, 682–696. [Google Scholar] [CrossRef] [PubMed]
- Yakes, F.M.; Van Houten, B. Mitochondrial DNA Damage Is More Extensive and Persists Longer than Nuclear DNA Damage in Human Cells Following Oxidative Stress. Proc. Natl. Acad. Sci. USA 1997, 94, 514–519. [Google Scholar] [CrossRef] [PubMed]
- Richter, C.; Park, J.W.; Ames, B.N. Normal Oxidative Damage to Mitochondrial and Nuclear DNA Is Extensive. Proc. Natl. Acad. Sci. USA 1988, 85, 6465–6467. [Google Scholar] [CrossRef] [PubMed]
- Shi, W.H.; Ye, M.J.; Qin, N.X.; Zhou, Z.Y.; Zhou, X.Y.; Xu, N.X.; Chen, S.C.; Li, S.Y.; Xu, C.M. Associations of Sperm MtDNA Copy Number, DNA Fragmentation Index, and Reactive Oxygen Species with Clinical Outcomes in ART Treatments. Front. Endocrinol. 2022, 13, 849534. [Google Scholar] [CrossRef] [PubMed]
- Amaral, A.; Ramalho-Santos, J.; St John, J.C. The Expression of Polymerase γ and Mitochondrial Transcription Factor A and the Regulation of Mitochondrial DNA Content in Mature Human Sperm. Hum. Reprod. 2007, 22, 1585–1596. [Google Scholar] [CrossRef]
- May-Panloup, P.; Chrétien, M.F.; Savagner, F.; Vasseur, C.; Jean, M.; Malthièry, Y.; Reynier, P. Increased Sperm Mitochondrial DNA Content in Male Infertility. Hum. Reprod. 2003, 18, 550–556. [Google Scholar] [CrossRef] [PubMed]
- Díez-Sánchez, C.; Ruiz-Pesini, E.; Lapeña, A.C.; Montoya, J.; Pérez-Martos, A.; Enríquez, J.A.; López-Pérez, M.J. Mitochondrial DNA Content of Human Spermatozoa. Biol. Reprod. 2003, 68, 180–185. [Google Scholar] [CrossRef] [PubMed]
- Bonanno, O.; Romeo, G.; Asero, P.; Pezzino, F.M.; Castiglione, R.; Burrello, N.; Sidoti, G.; Frajese, G.V.; Vicari, E.; D’Agata, R. Sperm of Patients with Severe Asthenozoospermia Show Biochemical, Molecular and Genomic Alterations. Reproduction 2016, 152, 695–704. [Google Scholar] [CrossRef] [PubMed]
- Song, G.J.; Lewis, V. Mitochondrial DNA Integrity and Copy Number in Sperm from Infertile Men. Fertil. Steril. 2008, 90, 2238–2244. [Google Scholar] [CrossRef] [PubMed]
- Tian, M.; Bao, H.; Martin, F.L.; Zhang, J.; Liu, L.; Huang, Q.; Shen, H. Association of DNA Methylation and Mitochondrial DNA Copy Number with Human Semen Quality. Biol. Reprod. 2014, 91, 101. [Google Scholar] [CrossRef] [PubMed]
- Faja, F.; Carlini, T.; Coltrinari, G.; Finocchi, F.; Nespoli, M.; Pallotti, F.; Lenzi, A.; Lombardo, F.; Paoli, D. Human Sperm Motility: A Molecular Study of Mitochondrial DNA, Mitochondrial Transcription Factor A Gene and DNA Fragmentation. Mol. Biol. Rep. 2019, 46, 4113–4121. [Google Scholar] [CrossRef] [PubMed]
- Wu, H.; Whitcomb, B.W.; Huffman, A.; Brandon, N.; Labrie, S.; Tougias, E.; Lynch, K.; Rahil, T.; Sites, C.K.; Richard Pilsner, J. Associations of Sperm Mitochondrial DNA Copy Number and Deletion Rate with Fertilization and Embryo Development in a Clinical Setting. Hum. Reprod. 2019, 34, 163–170. [Google Scholar] [CrossRef] [PubMed]
- Kao, S.H.; Chao, H.T.; Wei, Y.H. Mitochondrial Deoxyribonucleic Acid 4977-Bp Deletion Is Associated with Diminished Fertility and Motility of Human Sperm. Biol. Reprod. 1995, 52, 729–736. [Google Scholar] [CrossRef] [PubMed]
- Lestienne, P.; Reynier, P.; Chrétien, M.F.; Penisson-Besnier, I.; Malthièry, Y.; Rohmer, V. Oligoasthenospermia Associated with Multiple Mitochondrial DNA Rearrangements. Mol. Hum. Reprod. 1997, 3, 811–814. [Google Scholar] [CrossRef] [PubMed]
- Al Zoubi, M.S.; Al-Batayneh, K.; Alsmadi, M.; Rashed, M.; Al-Trad, B.; Al Khateeb, W.; Aljabali, A.; Otoum, O.; Al-Talib, M.; Batiha, O. 4,977-Bp Human Mitochondrial DNA Deletion Is Associated with Asthenozoospermic Infertility in Jordan. Andrologia 2020, 52, e13379. [Google Scholar] [CrossRef] [PubMed]
- Al Zoubi, M.S.; Al-Talafha, A.M.; Al Sharu, E.; Al-Trad, B.; Alzu’Bi, A.; AbuAlarjah, M.I.; Shehab, Q.; Alsmadi, M.; Al-Batayneh, K.M. Correlation of Sperm Mitochondrial DNA 7345 Bp and 7599 Bp Deletions with Asthenozoospermia in Jordanian Population. J. Reprod. Infertil. 2021, 22, 165–172. [Google Scholar] [CrossRef] [PubMed]
- Ambulkar, P.S.; Chuadhari, A.R.; Pal, A.K. Association of Large Scale 4977-Bp “common” Deletions in Sperm Mitochondrial DNA with Asthenozoospermia and Oligoasthenoteratozoospermia. J. Hum. Reprod. Sci. 2016, 9, 35–40. [Google Scholar] [CrossRef] [PubMed]
- Talebi, E.; Karimian, M.; Nikzad, H. Association of Sperm Mitochondrial DNA Deletions with Male Infertility in an Iranian Population. Mitochondrial DNA Part A DNA Mapp. Seq. Anal. 2018, 29, 615–623. [Google Scholar] [CrossRef] [PubMed]
- Al Smadi, M.A.; Hammadeh, M.E.; Solomayer, E.; Batiha, O.; Altalib, M.M.; Jahmani, M.Y.; Shboul, M.A.; Nusair, B.; Amor, H. Impact of Mitochondrial Genetic Variants in ND1, ND2, ND5, and ND6 Genes on Sperm Motility and Intracytoplasmic Sperm Injection (ICSI) Outcomes. Reprod. Sci. 2021, 28, 1540–1555. [Google Scholar] [CrossRef] [PubMed]
- Kao, S.H.; Chao, H.T.; Wei, Y.H. Multiple Deletions of Mitochondrial DNA Are Associated with the Decline of Motility and Fertility of Human Spermatozoa. Mol. Hum. Reprod. 1998, 4, 657–666. [Google Scholar] [CrossRef] [PubMed]
- Karimian, M.; Babaei, F. Large-Scale MtDNA Deletions as Genetic Biomarkers for Susceptibility to Male Infertility: A Systematic Review and Meta-Analysis. Int. J. Biol. Macromol. 2020, 158, 85–93. [Google Scholar] [CrossRef] [PubMed]
- Holyoake, A.J.; Sin, I.L.; Benny, P.S.; Sin, F.Y.T. Association of a Novel Human MtDNA ATPase6 Mutation with Immature Sperm Cells. Andrologia 1999, 31, 339–345. [Google Scholar] [CrossRef]
- Siwar, B.G.; Myriam, G.; Afif, B.M.; Emna, M.R.; Nozha, C.; Afifa, S.; Faiza, F.; Leila, A.K. Two Novel Mutations in COII and TRNAHis Mitochondrial Genes in Asthenozoospermic Infertiles Men. Biochem. Biophys. Res. Commun. 2014, 450, 610–615. [Google Scholar] [CrossRef] [PubMed]
- Mao, G.H.; Wang, Y.N.; Xu, M.; Wang, W.L.; Tan, L.; Tao, S.B. Polymorphisms in the MT-ATP6 and MT-CYB Genes in in Vitro Fertilization Failure. Mitochondrial DNA 2015, 26, 20–24. [Google Scholar] [CrossRef] [PubMed]
- Selvi Rani, D.; Vanniarajan, A.; Gupta, N.J.; Chakravarty, B.; Singh, L.; Thangaraj, K. A Novel Missense Mutation C11994T in the Mitochondrial ND4 Gene as a Cause of Low Sperm Motility in the Indian Subcontinent. Fertil. Steril. 2006, 86, 1783–1785. [Google Scholar] [CrossRef]
- Thangaraj, K.; Joshi, M.B.; Reddy, A.G.; Rasalkar, A.A.; Singh, L. Sperm Mitochondrial Mutations as a Cause of Low Sperm Motility. J. Androl. 2003, 24, 388–392. [Google Scholar] [CrossRef] [PubMed]
- Ni, F.; Zhou, Y.; Zhang, W.X.; Wang, X.M.; Song, X.M.; Jiang, H. Mitochondrial Variations in the MT-ND4 and MT-TL1 Genes Are Associated with Male Infertility. Syst. Biol. Reprod. Med. 2017, 63, 2–6. [Google Scholar] [CrossRef] [PubMed]
- Kao, S.H.; Chao, H.T.; Liu, H.W.; Liao, T.L.; Wei, Y.H. Sperm Mitochondrial DNA Depletion in Men with Asthenospermia. Fertil. Steril. 2004, 82, 66–73. [Google Scholar] [CrossRef] [PubMed]
- Zhang, G.; Wang, Z.; Ling, X.; Zou, P.; Yang, H.; Chen, Q.; Zhou, N.; Sun, L.; Gao, J.; Zhou, Z.; et al. Mitochondrial Biomarkers Reflect Semen Quality: Results from the MARCHS Study in Chongqing, China. PLoS ONE 2016, 11, e0168823. [Google Scholar] [CrossRef] [PubMed]
- Moustakli, E.; Zikopoulos, A.; Skentou, C.; Bouba, I.; Tsirka, G.; Stavros, S.; Vrachnis, D.; Vrachnis, N.; Potiris, A.; Georgiou, I.; et al. Sperm Mitochondrial Content and Mitochondrial DNA to Nuclear DNA Ratio Are Associated with Body Mass Index and Progressive Motility. Biomedicines 2023, 11, 3014. [Google Scholar] [CrossRef] [PubMed]
- Ieremiadou, F.; Rodakis, G.C. Correlation of the 4977 Bp Mitochondrial DNA Deletion with Human Sperm Dysfunction. BMC Res. Notes 2009, 2, 18. [Google Scholar] [CrossRef]
- Hosseinzadeh Colagar, A.; Karimi, F. Large Scale Deletions of the Mitochondrial DNA in Astheno, Asthenoterato and Oligoasthenoterato-Spermic Men. Mitochondrial DNA 2014, 25, 321–328. [Google Scholar] [CrossRef]
- Guo, Z.; **, C.; Yao, Z.; Wang, Y.; Xu, B. Analysis of the Mitochondrial 4977 Bp Deletion in Patients with Hepatocellular Carcinoma. Balk. J. Med. Genet. 2017, 20, 81–86. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; McGoldrick, L.L.; Chung, J.J. Sperm Ion Channels and Transporters in Male Fertility and Infertility. Nat. Rev. Urol. 2021, 18, 46–66. [Google Scholar] [CrossRef] [PubMed]
- Cavarocchi, E.; Whitfield, M.; Saez, F.; Touré, A. Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives. Int. J. Mol. Sci. 2022, 23, 3926. [Google Scholar] [CrossRef] [PubMed]
- Avidan, N.; Tamary, H.; Dgany, O.; Cattan, D.; Pariente, A.; Thulliez, M.; Borot, N.; Moati, L.; Barthelme, A.; Shalmon, L.; et al. CATSPER2, a Human Autosomal Nonsyndromic Male Infertility Gene. Eur. J. Hum. Genet. 2003, 11, 497–502. [Google Scholar] [CrossRef] [PubMed]
- Smith, J.F.; Syritsyna, O.; Fellousc, M.; Serres, C.; Mannowetz, N.; Kirichok, Y.; Lishko, P.V. Disruption of the Principal, Progesterone-Activated Sperm Ca2+ Channel in a CatSper2-Deficient Infertile Patient. Proc. Natl. Acad. Sci. USA 2013, 110, 6823–6828. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Malekpour, M.; Al-Madani, N.; Kahrizi, K.; Zanganeh, M.; Mohseni, M.; Mojahedi, F.; Daneshi, A.; Najmabadi, H.; Smith, R.J.H. Sensorineural Deafness and Male Infertility: A Contiguous Gene Deletion Syndrome. J. Med. Genet. 2007, 44, 233–240. [Google Scholar] [CrossRef]
- Avenarius, M.R.; Hildebrand, M.S.; Zhang, Y.; Meyer, N.C.; Smith, L.L.H.; Kahrizi, K.; Najmabadi, H.; Smith, R.J.H. Human Male Infertility Caused by Mutations in the CATSPER1 Channel Protein. Am. J. Hum. Genet. 2009, 84, 505–510. [Google Scholar] [CrossRef] [PubMed]
- Cohen, R.; Buttke, D.E.; Asano, A.; Mukai, C.; Nelson, J.L.; Ren, D.; Miller, R.J.; Cohen-Kutner, M.; Atlas, D.; Travis, A.J. Lipid Modulation of Calcium Flux through CaV2.3 Regulates Acrosome Exocytosis and Fertilization. Dev. Cell 2014, 28, 310–321. [Google Scholar] [CrossRef]
- Höglund, P.; Hihnala, S.; Kujala, M.; Tiitinen, A.; Dunkel, L.; Holmberg, C. Disruption of the SLC26A3-Mediated Anion Transport Is Associated with Male Subfertility. Fertil. Steril. 2006, 85, 232–235. [Google Scholar] [CrossRef] [PubMed]
- Wedenoja, S.; Khamaysi, A.; Shimshilashvili, L.; Anbtawe-Jomaa, S.; Elomaa, O.; Toppari, J.; Höglund, P.; Aittomäki, K.; Holmberg, C.; Hovatta, O.; et al. A Missense Mutation in SLC26A3 Is Associated with Human Male Subfertility and Impaired Activation of CFTR. Sci. Rep. 2017, 7, 14208. [Google Scholar] [CrossRef] [PubMed]
- Dirami, T.; Rode, B.; Jollivet, M.; Da Silva, N.; Escalier, D.; Gaitch, N.; Norez, C.; Tuffery, P.; Wolf, J.P.; Becq, F.; et al. Missense Mutations in SLC26A8, Encoding a Sperm-Specific Activator of CFTR, Are Associated with Human Asthenozoospermia. Am. J. Hum. Genet. 2013, 92, 760–766. [Google Scholar] [CrossRef] [PubMed]
- De Pinto, V.; Messina, A.; Lane, D.J.R.; Lawen, A. Voltage-Dependent Anion-Selective Channel (VDAC) in the Plasma Membrane. FEBS Lett. 2010, 584, 1793–1799. [Google Scholar] [CrossRef]
- Xu, A.; Hua, Y.; Zhang, J.; Chen, W.; Zhao, K.; ** Review. J. Assist. Reprod. Genet. 2021, 38, 573–586. [Google Scholar] [CrossRef] [PubMed]
- Shang, Y.; Yan, J.; Tang, W.; Liu, C.; **ao, S.; Guo, Y.; Yuan, L.; Chen, L.; Jiang, H.; Guo, X.; et al. Mechanistic Insights into Acephalic Spermatozoa Syndrome–Associated Mutations in the Human SUN5 Gene. J. Biol. Chem. 2018, 293, 2395–2407. [Google Scholar] [CrossRef] [PubMed]
- Shang, Y.; Zhu, F.; Wang, L.; Ouyang, Y.C.; Dong, M.Z.; Liu, C.; Zhao, H.; Cui, X.; Ma, D.; Zhang, Z.; et al. Essential Role for SUN5 in Anchoring Sperm Head to the Tail. Elife 2017, 6, e28199. [Google Scholar] [CrossRef] [PubMed]
- Zhu, F.; Liu, C.; Wang, F.; Yang, X.; Zhang, J.; Wu, H.; Zhang, Z.; He, X.; Zhang, Z.; Zhou, P.; et al. Mutations in PMFBP1 Cause Acephalic Spermatozoa Syndrome. Am. J. Hum. Genet. 2018, 103, 188–199. [Google Scholar] [CrossRef] [PubMed]
- Sha, Y.W.; Sha, Y.K.; Ji, Z.Y.; Mei, L.B.; Ding, L.; Zhang, Q.; Qiu, P.P.; Lin, S.B.; Wang, X.; Li, P.; et al. TSGA10 Is a Novel Candidate Gene Associated with Acephalic Spermatozoa. Clin. Genet. 2018, 93, 776–783. [Google Scholar] [CrossRef] [PubMed]
- Li, L.; Sha, Y.; Wang, X.; Li, P.; Wang, J.; Kee, K.; Wang, B. Whole-Exome Sequencing Identified a Homozygous BRDT Mutation in a Patient with Acephalic Spermatozoa. Oncotarget 2017, 8, 19914–19922. [Google Scholar] [CrossRef] [PubMed]
- Chen, H.; Zhu, Y.; Zhu, Z.; Zhi, E.; Lu, K.; Wang, X.; Liu, F.; Li, Z.; **a, W. Detection of Heterozygous Mutation in Hook Microtubule-Tethering Protein 1 in Three Patients with Decapitated and Decaudated Spermatozoa Syndrome. J. Med. Genet. 2018, 55, 150–157. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef]
- Li, Y.Z.; Li, N.; Liu, W.S.; Sha, Y.W.; Wu, R.F.; Tang, Y.L.; Zhu, X.S.; Wei, X.L.; Zhang, X.Y.; Wang, Y.F.; et al. Biallelic Mutations in Spermatogenesis and Centriole-Associated 1 like (SPATC1L) Cause Acephalic Spermatozoa Syndrome and Male Infertility. Asian J. Androl. 2022, 24, 67–72. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef]
- Sun, J.P.; Fang, J.Z.; Sun, X.P.; Yang, X.Y. Intracytoplasmic Sperm Injection for Patients with Special Types of Teratozoospermia: Analysis of Outcomes. Zhonghua Nan Ke Xue 2023, 29, 43–48. [Google Scholar] [PubMed]
- Jiang, M.; Gao, M.; Wu, C.; He, H.; Guo, X.; Zhou, Z.; Yang, H.; **ao, X.; Liu, G.; Sha, J. Lack of Testicular Seipin Causes Teratozoospermia Syndrome in Men. Proc. Natl. Acad. Sci. USA 2014, 111, 7054–7059. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.Y.; Lai, T.H.; Chen, M.F.; Lee, H.L.; Kuo, P.L.; Lin, Y.H. SEPT14 Mutations and Teratozoospermia: Genetic Effects on Sperm Head Morphology and DNA Integrity. J. Clin. Med. 2019, 8, 1297. [Google Scholar] [CrossRef] [PubMed]
- Ma, Y.; **e, N.; **e, D.; Sun, L.; Li, S.; Li, P.; Li, Y.; Li, J.; Dong, Z.; **e, X. A Novel Homozygous FBXO43 Mutation Associated with Male Infertility and Teratozoospermia in a Consanguineous Chinese Family. Fertil. Steril. 2019, 111, 909–917.e1. [Google Scholar] [CrossRef] [PubMed]
- Liu, L.; Yang, J.; Zhang, W.J.; Zhou, Y.L.; Zhao, G.J.; Huang, Y.; Tang, S.Y. The Identification of AMZ2 as a Candidate Causative Gene in a Severe Teratozoospermia Patient Characterized by Vacuolated Spermatozoa. Asian J. Androl. 2024, 26, 107–111. [Google Scholar] [CrossRef] [PubMed]
- Jiang, X.; Wang, X.; Zhang, X.; **ao, Z.; Zhang, C.; Liu, X.; Xu, J.; Li, D.; Shen, Y. A Homozygous RNF220 Mutation Leads to Male Infertility with Small-Headed Sperm. Gene 2019, 688, 13–18. [Google Scholar] [CrossRef] [PubMed]
- Fan, Y.; Huang, C.; Chen, J.; Chen, Y.; Wang, Y.; Yan, Z.; Yu, W.; Wu, H.; Yang, Y.; Nie, L.; et al. Mutations in CCIN Cause Teratozoospermia and Male Infertility. Sci. Bull. 2022, 67, 2112–2123. [Google Scholar] [CrossRef] [PubMed]
- Hua, J.; Guo, L.; Yao, Y.; Hu, W.; Wan, Y.Y.; Xu, B. Biallelic Mutations in WDR12 Are Associated with Male Infertility with Tapered-Head Sperm. Asian J. Androl. 2023, 25, 398–403. [Google Scholar] [CrossRef] [PubMed]
- Lin, Y.H.; Wang, Y.Y.; Lai, T.H.; Teng, J.L.; Lin, C.W.; Ke, C.C.; Yu, I.S.; Lee, H.L.; Chan, C.C.; Tung, C.H.; et al. Deleterious Genetic Changes in AGTPBP1 Result in Teratozoospermia with Sperm Head and Flagella Defects. J. Cell. Mol. Med. 2024, 28, e18031. [Google Scholar] [CrossRef] [PubMed]
- Dai, J.; Chen, Y.; Li, Q.; Zhang, T.; Zhou, Q.; Gong, F.; Lu, G.; Zheng, W.; Lin, G. Pathogenic Variant in ACTL7A Causes Severe Teratozoospermia Characterized by Bubble-Shaped Acrosomes and Male Infertility. Mol. Hum. Reprod. 2022, 28, gaac028. [Google Scholar] [CrossRef] [PubMed]
- Laan, M.; Kasak, L.; Punab, M. Translational Aspects of Novel Findings in Genetics of Male Infertility—Status Quo 2021. Br. Med. Bull. 2021, 140, 5–22. [Google Scholar] [CrossRef]
References | Mitochondrial Defects | Main Findings | Suggestions |
---|---|---|---|
[29,30,31,32,33,34,50,51,52] | Altered mtDNA content | High number of mtDNA copies in men with reduced sperm motility | Not recommended yet |
[35,37,39,40,41,42,53,54,55] | Large mtDNA deletions or single mutations in genes encoding mitochondrial proteins | Associations with reduced sperm motility | Not recommended yet |
Mechanism Involved | Genes Involved | Currently Used in Clinical Practice |
---|---|---|
Ion channels | CATSPER 1-2-ε, SLC26A3, SLC9C1, SLC26A8, VDAC2-3, SLO3, PKD1-2 | Recommended |
Proteins of the flagella | DNAH5, DNAH11, CCDC39, DNAI1, CCDC40, CCDC103, SPAG1, ZMYND10, ARMC4, CCDC151, DNAI2, RSPH1, RSPH3, DNAH1, DNAH2, DNAH6, DNAH8, DNAH9, DNAH17, CFAP70, CFAP43, CFAP44, CCDC114, RSPH4A, DNAAF1, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAAF6, TTC12, DNAJB13, LRRC6, AKAP3, AKAP4, FSIP2, CEP135, DZIP1, CFAP251, CFAP91, CFAP65, CFAP58, SPEF2, TTC21A, TTC29, CFAP69, QRICH2, AK7, WDR19, NDUFA13, ARMC2, SEPTIN12 | Recommended |
Other causes | GAPDS, ARL2BP, CTE1/DRC5, ADGB, DNALI1, CFAP61, DRC1, CEP78, DNAH10, CFAP47, STK33, DNHD1, CFAP57, LRRC46, WDR63, CFAP206, SPAG6, IFT74, DNALI1, CCDC40, RSPH1, GALNTL5 | Not Recommended Yet |
Form of AZS | Genes Involved | Currently Used in Clinical Practice |
MMAF without PCD | DNAH1, DNAH2, DNAH6, DNAH8, DNAH9, DNAH17, CFAP70, CFAP43, CFAP44, AKAP3, AKAP4, FSIP2, CEP135, DZIP1, CFAP251, CFAP91, CFAP65, CFAP58, SPEF2, ARMC2, CFAP69, QRICH2, SEPTIN12, TTC29 | Recommended |
Form of Abnormal Sperm Morphology | Genes Involved | Current Analysis in Clinical Practice |
---|---|---|
Macrozoospermia | AURKC | Recommended |
ZMYND15, NUP210L, MEIKIN, ADAD2, MDC1 | Not recommended yet | |
Globozoospermia | DPY19L2, SPATA16, PICK1, ZPBP, CDC62 | Recommended |
C2CD6, CCIN, C7orf61, DNAH17, GGN, CCNB3, PIWIL4, CHPT1, SSFA2, SPACA1, SPATA20, FSIP2 | Not recommended yet | |
Acephalic spermatozoa syndrome | SUN5, PMFBP1, TSGA10 | Recommended |
BDRT, HOOK1, CEP112, ACTRT1, SPATC1L, SPATA20 | Not recommended yet | |
Other forms of abnormal sperm morphology | BSCL2, SEPTIN14, FBOX43, AMZ2, RNF220, CALICIN, WDR12, ACTL7A, SPATA6 | Not recommended yet |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Graziani, A.; Rocca, M.S.; Vinanzi, C.; Masi, G.; Grande, G.; De Toni, L.; Ferlin, A. Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence. Genes 2024, 15, 600. https://doi.org/10.3390/genes15050600
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. 2024; 15(5):600. https://doi.org/10.3390/genes15050600
Chicago/Turabian StyleGraziani, Andrea, Maria Santa Rocca, Cinzia Vinanzi, Giulia Masi, Giuseppe Grande, Luca De Toni, and Alberto Ferlin. 2024. "Genetic Causes of Qualitative Sperm Defects: A Narrative Review of Clinical Evidence" Genes 15, no. 5: 600. https://doi.org/10.3390/genes15050600