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Patient with multiple morphological abnormalities of sperm flagella caused by a novel ARMC2 mutation has a favorable pregnancy outcome from intracytoplasmic sperm injection

  • Genetics
  • Published:
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Abstract

Purpose

To investigate the potential genetic cause in a primary infertility patient with multiple morphological abnormalities of sperm flagella (MMAF).

Methods

The patient’s sperm was observed by light and electron microscopy. Whole-exome sequencing (WES) was carried out to identify candidate genes. Then, the mutation found by WES was verified by Sanger sequencing. The proteins interacting with ARMC2 were revealed by co-immunoprecipitation (co-IP) and mass spectrometry. Intracytoplasmic sperm injection (ICSI) was carried out to achieve successful pregnancy.

Results

Typical MMAF phenotype (absent, short, coiled, bent irregular flagella) was shown in the patient’s sperm. A novel homozygous mutation in ARMC2 (c.1264C > T) was identified. The proteins interacting with ARMC2 we found were CEP78, PGAM5, RHOA, FXR1, and SKIV2L2. The ICSI therapy was successful, and boy-girl twins were given birth.

Conclusion

We found a novel mutation in ARMC2 which led to MMAF and male infertility. This is the first report of ICSI outcome of patient harboring ARMC2 mutation. The interacting proteins indicated that ARMC2 might be involved in multiple processes of spermatogenesis.

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References

  1. Coutton C, Escoffier J, Martinez G, Arnoult C, Ray PF. Teratozoospermia: spotlight on the main genetic actors in the human. Hum Reprod Update. 2015;21:455–85.

    Article  CAS  Google Scholar 

  2. Ben Khelifa M, Coutton C, Zouari R, Karaouzène T, Rendu J, Bidart M, Yassine S, Pierre V, Delaroche J, Hennebicq S, Grunwald D, Escalier D, Pernet-Gallay K, Jouk PS, Thierry-Mieg N, Touré A, Arnoult C, Ray PF. Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2014;94:95–104.

    Article  CAS  Google Scholar 

  3. Tang S, Wang X, Li W, Yang X, Li Z, Liu W, Li C, Zhu Z, Wang L, Wang J, Zhang L, Sun X, Zhi E, Wang H, Li H, Jin L, Luo Y, Wang J, Yang S, Zhang F. Biallelic mutations in CFAP43 and CFAP44 cause male infertility with multiple morphological abnormalities of the sperm flagella. Am J Hum Genet. 2017;100:854–64.

    Article  CAS  Google Scholar 

  4. Li W, Wu H, Li F, Tian S, Kherraf ZE, Zhang J, Ni X, Lv M, Liu C, Tan Q, Shen Y, Amiri-Yekta A, Cazin C, Zhang J, Liu W, Zheng Y, Cheng H, Wu Y, Wang J, Gao Y, Chen Y, Zha X, Jin L, Liu M, He X, Ray PF, Cao Y, Zhang F. Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice. J Med Genet. 2020;57:89–95.

    Article  CAS  Google Scholar 

  5. Li W, He X, Yang S, Liu C, Wu H, Liu W, Lv M, Tang D, Tan J, Tang S, Chen Y, Wang J, Zhang Z, Wang H, Jin L, Zhang F, Cao Y. Biallelic mutations of CFAP251 cause sperm flagellar defects and human male infertility. J Hum Genet. 2019;64:49–54.

    Article  CAS  Google Scholar 

  6. Liu W, He X, Yang S, Zouari R, Wang J, Wu H, Kherraf ZE, Liu C, Coutton C, Zhao R, Tang D, Tang S, Lv M, Fang Y, Li W, Li H, Zhao J, Wang X, Zhao S, Zhang J, Arnoult C, Jin L, Zhang Z, Ray PF, Cao Y, Zhang F. Bi-allelic mutations in TTC21A induce asthenoteratospermia in humans and mice. Am J Hum Genet. 2019;104:738–48.

    Article  CAS  Google Scholar 

  7. Liu C, He X, Liu W, Yang S, Wang L, Li W, Wu H, Tang S, Ni X, Wang J, Gao Y, Tian S, Zhang L, Cong J, Zhang Z, Tan Q, Zhang J, Li H, Zhong Y, Lv M, Li J, Jin L, Cao Y, Zhang F. Bi-allelic mutations in TTC29 cause male subfertility with asthenoteratospermia in humans and mice. Am J Hum Genet. 2019;105:1168–81.

    Article  CAS  Google Scholar 

  8. Coutton C, Martinez G, Kherraf ZE, Amiri-Yekta A, Boguenet M, Saut A, He X, Zhang F, Cristou-Kent M, Escoffier J, Bidart M, Satre V, Conne B, Fourati Ben Mustapha S, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, Pernet-Gallay K, Bonhivers M, Hennebicq S, Rives N, Dulioust E, Touré A, Gourabi H, Cao Y, Zouari R, Hosseini SH, Nef S, Thierry-Mieg N, Arnoult C, Ray PF. Bi-allelic mutations in ARMC2 lead to severe astheno-teratozoospermia due to sperm flagellum malformations in humans and mice. Am J Hum Genet. 2019;104:331–40.

    Article  CAS  Google Scholar 

  9. Lu S, Gu Y, Wu Y, Yang S, Li C, Meng L, Yuan W, Jiang T, Zhang X, Li Y, Wang C, Liu M, Ye L, Guo X, Shen H, Yang X, Tan Y, Hu Z. Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly. Cell Discov. 2021;7:110.

    Article  CAS  Google Scholar 

  10. Castaneda JM, Hua R, Miyata H, Oji A, Guo Y, Cheng Y, Zhou T, Guo X, Cui Y, Shen B, Wang Z, Hu Z, Zhou Z, Sha J, Prunskaite-Hyyrylainen R, Yu Z, Ramirez-Solis R, Ikawa M, Matzuk MM, Liu M. TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa. Proc Natl Acad Sci U S A. 2017;114:E5370-5370E5378.

    Article  CAS  Google Scholar 

  11. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  12. Chemes HE, Brugo S, Zanchetti F, Carrere C, Lavieri JC. Dysplasia of the fibrous sheath: an ultrastructural defect of human spermatozoa associated with sperm immotility and primary sterility. Fertil Steril. 1987;48:664–9.

    Article  CAS  Google Scholar 

  13. Khan I, Dil S, Zhang H, Zhang B, Khan T, Zeb A, Zhou J, Nawaz S, Zubair M, Khan K, Ma H, Shi Q. A novel stop-gain mutation in ARMC2 is associated with multiple morphological abnormalities of the sperm flagella. Reprod Biomed Online. 2021;43:913–9.

    Article  CAS  Google Scholar 

  14. Darde TA, Lecluze E, Lardenois A, Stévant I, Alary N, Tüttelmann F, Collin O, Nef S, Jégou B, Rolland AD, Chalmel F. The ReproGenomics Viewer: a multi-omics and cross-species resource compatible with single-cell studies for the reproductive science community. Bioinformatics. 2019;35:3133–9.

    Article  CAS  Google Scholar 

  15. Teves ME, Nagarkatti-Gude DR, Zhang Z, Strauss JF 3rd. Mammalian axoneme central pair complex proteins: broader roles revealed by gene knockout phenotypes. Cytoskeleton (Hoboken). 2016;73:3–22.

    Article  CAS  Google Scholar 

  16. Peifer M, Berg S, Reynolds AB. A repeating amino acid motif shared by proteins with diverse cellular roles. Cell. 1994;76:789–91.

    Article  CAS  Google Scholar 

  17. Tewari R, Bailes E, Bunting KA, Coates JC. Armadillo-repeat protein functions: questions for little creatures. Trends Cell Biol. 2010;20:470–81.

    Article  CAS  Google Scholar 

  18. Liu Y, Zhang L, Li W, Huang Q, Yuan S, Li Y, Liu J, Zhang S, Pin G, Song S, Ray PF, Arnoult C, Cho C, Garcia-Reyes B, Knippschild U, Strauss JF, Zhang Z. The sperm-associated antigen 6 interactome and its role in spermatogenesis. Reproduction. 2019;158:181–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu H, Wang J, Cheng H, Gao Y, Liu W, Zhang Z, Jiang H, Li W, Zhu F, Lv M, Liu C, Tan Q, Zhang X, Wang C, Ni X, Chen Y, Song B, Zhou P, Wei Z, Zhang F, He X, Cao Y. Patients with severe asthenoteratospermia carrying SPAG6 or RSPH3 mutations have a positive pregnancy outcome following intracytoplasmic sperm injection. J Assist Reprod Genet. 2020;37:829–40.

    Article  Google Scholar 

  20. Pausch H, Venhoranta H, Wurmser C, Hakala K, Iso-Touru T, Sironen A, Vingborg RK, Lohi H, Söderquist L, Fries R, Andersson M. A frameshift mutation in ARMC3 is associated with a tail stump sperm defect in Swedish Red (Bos taurus) cattle. BMC Genet. 2016;17:49.

    Article  Google Scholar 

  21. Gonçalves AB, Hasselbalch SK, Joensen BB, Patzke S, Martens P, Ohlsen SK, Quinodoz M, Nikopoulos K, Suleiman R, Damsø Jeppesen MP, Weiss C, Christensen ST, Rivolta C, Andersen JS, Farinelli P, Pedersen LB. CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels. Elife. 2021;10:e63731.

    Article  Google Scholar 

  22. Ascari G, Peelman F, Farinelli P, Rosseel T, Lambrechts N, Wunderlich KA, Wagner M, Nikopoulos K, Martens P, Balikova I, Derycke L, Holtappels G, Krysko O, Van Laethem T, De Jaegere S, Guillemyn B, De Rycke R, De Bleecker J, Creytens D, Van Dorpe J, Gerris J, Bachert C, Neuhofer C, Walraedt S, Bischoff A, Pedersen LB, Klopstock T, Rivolta C, Leroy BP, De Baere E, Coppieters F. Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility. Hum Mutat. 2020;41:998–1011.

    Article  CAS  Google Scholar 

  23. Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H, Huang L, Zhou C, Cai X, Fu C, Duan L, Wang X, Liu L, Liu X, Shen Y, Zhu Y, Chen Q. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell. 2014;54:362–77.

    Article  CAS  Google Scholar 

  24. Alkhaled Y, Laqqan M, Tierling S, Lo Porto C, Amor H, Hammadeh ME. Impact of cigarette-smoking on sperm DNA methylation and its effect on sperm parameters. Andrologia. 2018. https://doi.org/10.1111/and.12950.

  25. Fiedler SE, Bajpai M, Carr DW. Identification and characterization of RHOA-interacting proteins in bovine spermatozoa. Biol Reprod. 2008;78:184–92.

    Article  CAS  Google Scholar 

  26. Huot ME, Mazroui R, Leclerc P, Khandjian EW. Developmental expression of the fragile X-related 1 proteins in mouse testis: association with microtubule elements. Hum Mol Genet. 2001;10:2803–11.

    Article  CAS  Google Scholar 

  27. Osman BA, Kawashima A, Tamba M, Satoh E, Kato Y, Iki A, Konishi K, Matsuda M, Okamura N. Localization of a novel RNA-binding protein, SKIV2L2, to the nucleus in the round spermatids of mice. J Reprod Dev. 2011;57:457–67.

    Article  CAS  Google Scholar 

  28. Wambergue C, Zouari R, Fourati Ben Mustapha S, Martinez G, Devillard F, Hennebicq S, Satre V, Brouillet S, Halouani L, Marrakchi O, Makni M, Latrous H, Kharouf M, Amblard F, Arnoult C, Ray PF, Coutton C. Patients with multiple morphological abnormalities of the sperm flagella due to DNAH1 mutations have a good prognosis following intracytoplasmic sperm injection. Hum Reprod. 2016;31:1164–72.

    Article  CAS  Google Scholar 

  29. Wang J, Zhang C, Tang H, Zheng A, Li H, Yang S, Xiang J. Successful results of intracytoplasmic sperm injection of a Chinese patient with multiple morphological abnormalities of sperm flagella caused by a novel splicing mutation in CFAP251. Front Genet. 2022;12:783790.

    Article  Google Scholar 

  30. Sha YW, Xu X, Mei LB, Li P, Su ZY, He XQ, Li L. A homozygous CEP135 mutation is associated with multiple morphological abnormalities of the sperm flagella (MMAF). Gene. 2017;633:48–53.

    Article  CAS  Google Scholar 

  31. Wang W, Tu C, Nie H, Meng L, Li Y, Yuan S, Zhang Q, Du J, Wang J, Gong F, Fan L, Lu GX, Lin G, Tan YQ. Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations. J Med Genet. 2019;56:750–7.

    Article  CAS  Google Scholar 

  32. Wang W, Tian S, Nie H, Tu C, Liu C, Li Y, Li D, Yang X, Meng L, Hu T, Zhang Q, Du J, Fan L, Lu G, Lin G, Zhang F, Tan YQ. CFAP65 is required in the acrosome biogenesis and mitochondrial sheath assembly during spermiogenesis. Hum Mol Genet. 2021;30:2240–54.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank Li Wang and Dandan Song in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University for their technical support. This work was supported by the General Project of Natural Science Foundation of Xinjiang Uygur Autonomous Region (2021D01C297), Suzhou Health Talent Cultivation Project (GSWS2019053), Suzhou Science and Technology Development Plan Project (SYSD2020129), Innovative and Entrepreneurial Doctor grant from Jiangsu Province (JSSCBS20211586).

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Author notes

  1. Jiaxiong Wang, Xiaoran Liu and Ce Zhang contributed equally to this work.

Authors and Affiliations

  1. Center for Reproduction and Genetics, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215002, China

    Jiaxiong Wang, Ce Zhang, Yongle Xu, Weizhuo Wang, Hong Li & Shenmin Yang

  2. Department of Reproductive Medicine Center, The First Affiliated Hospital of XinJiang Medical University, Urumqi, 830054, Xinjiang, China

    Xiaoran Liu & Jing Zhao

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  1. Jiaxiong Wang
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  2. Xiaoran Liu
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Contributions

J.W. conceived and designed the experiments and wrote the manuscript. X.L. and J.Z. performed genetic analysis. C.Z. and W.W. performed bioinformatic analyses. Y.X., H.L., and S.Y. contributed to the discussion of the data. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Shenmin Yang or Jing Zhao.

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This study was approved by the Affiliated Suzhou Hospital of Nanjing Medical University and the First Affiliated Hospital of Xinjiang Medical University.

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Written informed consent was obtained from all of the subjects and their family members participating in the study.

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The authors declare no competing interests.

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Wang, J., Liu, X., Zhang, C. et al. Patient with multiple morphological abnormalities of sperm flagella caused by a novel ARMC2 mutation has a favorable pregnancy outcome from intracytoplasmic sperm injection. J Assist Reprod Genet 39, 1673–1681 (2022). https://doi.org/10.1007/s10815-022-02516-x

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