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Cited by 42Sperm and Testicular FunctionGenomics and Rare DiseasesReproductive Biology and Fertility

Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player

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Celse, Tristan, Cazin, Caroline, Mietton, Flore, Martinez, Guillaume, Martinez, Delphine, Thierry-Mieg, Nicolas, Septier, Amandine, Guillemain, Catherine +35 more·2021·Human Genetics
DOI 10.1007/s00439-020-02229-0
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Abstract

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

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  • No genetic mutation has been identified in patients with <50% globozoospermia.

    “No genetic mutation has been identified in patients with < 50% globozoospermia [29].”

    From Recommendations for Human Sperm Morphology Assessment in 2025: An Expert Review From the French BLEFCO Group (2026) · cites this paper as [29]

    The Diagnostic performances section reports no positive DPY19L2 diagnosis among the study’s patients with less than 50% globozoospermia. The claim omits those limits: the finding concerns DPY19L2 screening in this cohort, not an absence of any genetic mutation in all such patients. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 44

  1. Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248- 249. https ://doi.org/10.1038/nmeth 0410-248 · DOI · Paper page
  2. Alimohammadi F, Ebrahimi Nasab M, Rafaee A et al (2020) Dele- tion of dpy-19 like 2 (DPY19L2) gene is associated with total but not partial globozoospermia. Reprod Fertil Dev. https ://doi. org/10.1071/RD190 25 · DOI
  3. Anton-Lamprecht I, Kotzur B, Schopf E (1976) Round-headed human spermatozoa. Fertil Steril 27:685-693. https ://doi.org/10.1016/ s0015 -0282(16)41900 -x 1 · DOI
  4. Buettner FFR, Ashikov A, Tiemann B et al (2013) C. elegans DPY- 19 is a C-mannosyltransferase glycosylating thrombospondin repeats. Mol Cell 50:295-302. https ://doi.org/10.1016/j.molce l.2013.03.003 · DOI
  5. Chemes HE (2018) Phenotypic varieties of sperm pathology: genetic abnormalities or environmental influences can result in different patterns of abnormal spermatozoa. Anim Reprod Sci 194:41-56. https ://doi.org/10.1016/j.anire prosc i.2018.04.074 · DOI
  6. Chen S, Zhou Y, Chen Y, Gu J (2018) Fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics 34:i884-i890. https ://doi. org/10.1093/bioin forma tics/bty56 0 · DOI
  7. Chianese C, Fino MG, Riera Escamilla A et al (2015) Comprehen- sive investigation in patients affected by sperm macrocephaly and globozoospermia. Andrology 3:203-212. https ://doi.org/10.1111/ andr.12016 · DOI
  8. Cooper TG, Noonan E, von Eckardstein S et al (2010) World Health Organization reference values for human semen characteristics* ‡. Hum Reprod Update 16:231-245. https ://doi.org/10.1093/humup d/dmp04 8 · DOI · Paper page
  9. Coutton C, Vieville G, Satre V et al (2012a) Multiplex ligation-depend- ent probe amplification (MLPA) et sondes « à façon » entièrement synthétiques. Guide pratique, recommandations et expérience au CHU de Grenoble. IRBM 33:227-235. https ://doi.org/10.1016/j. irbm.2012.04.004 · DOI
  10. Coutton C, Zouari R, Abada F et al (2012b) MLPA and sequence analysis of DPY19L2 reveals point mutations causing globozoo- spermia. Hum Reprod 27:2549-2558. https ://doi.org/10.1093/ humre p/des16 0 · DOI
  11. Coutton C, Abada F, Karaouzene T et al (2013) Fine characterisation of a recombination hotspot at the DPY19L2 locus and resolution of the paradoxical excess of duplications over deletions in the gen- eral population. PLoS Genet 9:e1003363. https ://doi.org/10.1371/ journ al.pgen.10033 63 · DOI
  12. Coutton C, Escoffier J, Martinez G et al (2015) Teratozoospermia: spotlight on the main genetic actors in the human. Hum Reprod Update 21:455-485. https ://doi.org/10.1093/humup d/dmv02 0 · DOI · Paper page
  13. Dam AHDM, Koscinski I, Kremer JAM et al (2007) Homozygous mutation in SPATA16 is associated with male infertility in human globozoospermia. Am J Hum Genet 81:813-820. https ://doi. org/10.1086/52131 · DOI
  14. Dam AH, Ramos L, Dijkman HB et al (2011) Morphology of partial globozoospermia. J Androl 32:199-206. https ://doi.org/10.2164/ jandr ol.109.00953 0 · DOI
  15. den Dunnen JT, Antonarakis SE (2000) Mutation nomenclaturess extensions and suggestions to describe complex mutations: a dis- cussion. Hum Mutat 15:7-12. https ://doi.org/10.1002/(SICI)1098- 1004(20000 1)15:1%3c7::AID-HUMU4 %3e3.0.CO;2-N Desmet F-O, Hamroun D, Lalande M et al (2009) Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67. https ://doi.org/10.1093/nar/gkp21 5 · DOI
  16. Elinati E, Kuentz P, Redin C et al (2012) Globozoospermia is mainly due to DPY19L2 deletion via non-allelic homologous recombi- nation involving two recombination hotspots. Hum Mol Genet 21:3695-3702. https ://doi.org/10.1093/hmg/dds20 0 · DOI
  17. ElInati E, Fossard C, Okutman O et al (2016) A new mutation identified in SPATA16 in two globozoospermic patients. J Assist Reprod Genet 33:815-820. https ://doi.org/10.1007/s1081 5-016-0715-3 · DOI
  18. Ghédir H, Ibala-Romdhane S, Okutman O et al (2016) Identification of a new DPY19L2 mutation and a better definition of DPY19L2 deletion breakpoints leading to globozoospermia. Mol Hum Reprod 22:35-45. https ://doi.org/10.1093/moleh r/gav06 1 · DOI
  19. Ghédir H, Braham A, Viville S et al (2019) Comparison of sperm morphology and nuclear sperm quality in SPATA16-and DPY19L2-mutated globozoospermic patients. Andrologia 51:e13277. https ://doi.org/10.1111/and.13277 · DOI
  20. Guan R, Wen X-Y, Wu J et al (2012) Knockdown of ZNF403 inhibits cell proliferation and induces G2/M arrest by modulating cell- cycle mediators. Mol Cell Biochem 365:211-222. https ://doi. org/10.1007/s1101 0-012-1262-6 · DOI
  21. Han T, Wang L, Tang W et al (2020) GGNBP1 ensures proper spermiogenesis in response to stress in mice. Biochem Bio- phys Res Commun 525:706-713. https ://doi.org/10.1016/j. bbrc.2020.02.118 · DOI
  22. Harbuz R, Zouari R, Pierre V et al (2011) A recurrent deletion of DPY19L2 causes infertility in man by blocking sperm head elon- gation and acrosome formation. Am J Hum Genet 88:351-361. https ://doi.org/10.1016/j.ajhg.2011.02.007 · DOI
  23. Jamsai D, Bianco DM, Smith SJ et al (2008) Characterization of gametogenetin 1 (GGN1) and its potential role in male fertility through the interaction with the ion channel regulator, cysteine- rich secretory protein 2 (CRISP2) in the sperm tail. Reproduction 135:751-759. https ://doi.org/10.1530/REP-07-0485 · DOI
  24. Jamsai D, O'Connor AE, DeBoer KD et al (2013) Loss of GGN leads to pre-implantation embryonic lethality and compromised male meiotic DNA double strand break repair in the mouse. PLoS ONE 8:e56955. https ://doi.org/10.1371/journ al.pone.00569 55 · DOI
  25. Kim S, Scheffler K, Halpern AL et al (2018) Strelka2: fast and accurate calling of germline and somatic variants. Nat Methods 15:591- 594. https ://doi.org/10.1038/s4159 2-018-0051-x · DOI
  26. Kopanos C, Tsiolkas V, Kouris A et al (2019) VarSome: the human genomic variant search engine. Bioinformatics 35:1978-1980. https ://doi.org/10.1093/bioin forma tics/bty89 7 · DOI
  27. Koscinski I, ElInati E, Fossard C et al (2011) DPY19L2 deletion as a major cause of globozoospermia. Am J Hum Genet 88:344-350. https ://doi.org/10.1016/j.ajhg.2011.01.018 · DOI
  28. Li H (2013) Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv:13033997 [q-bio]
  29. Li H, Handsaker B, Wysoker A et al (2009) The sequence alignment/ map format and SAMtools. Bioinformatics 25:2078-2079. https ://doi.org/10.1093/bioin forma tics/btp35 2 · DOI · Paper page
  30. Liu G, Shi Q-W, Lu G-X (2010) A newly discovered mutation in PICK1 in a human with globozoospermia. Asian J Androl 12:556-560. https ://doi.org/10.1038/aja.2010. · DOI
  31. Lu B, Bishop CE (2003) Mouse GGN1 and GGN3, two germ cell- specific proteins from the single gene Ggn, interact with mouse POG and play a role in spermatogenesis. J Biol Chem 278:16289- 16296. https ://doi.org/10.1074/jbc.M2110 23200 · DOI
  32. Mascarenhas MN, Flaxman SR, Boerma T et al (2012) National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLOS Med 9:e1001356. https ://doi.org/10.1371/journ al.pmed.10013 56 · DOI
  33. McLaren W, Gil L, Hunt SE et al (2016) The ensembl variant effect predictor. Genome Biol 17:122. https ://doi.org/10.1186/s1305 9-016-0974-4 · DOI · Paper page
  34. Modarres P, Tavalaee M, Ghaedi K, Nasr-Esfahani MH (2018) An overview of the globozoospermia as a multigenic identified syn- drome. IJFS. https ://doi.org/10.22074 /ijfs.2019.5561 · DOI
  35. Oud MS, Okutman Ö, Hendricks LAJ et al (2020) Exome sequenc- ing reveals novel causes as well as new candidate genes for human globozoospermia. Hum Reprod 35:240-252. https ://doi. org/10.1093/humre p/dez24 6 · DOI
  36. Pierre V, Martinez G, Coutton C et al (2012) Absence of Dpy19l2, a new inner nuclear membrane protein, causes globozoospermia in mice by preventing the anchoring of the acrosome to the nucleus. Development 139:2955-2965. https ://doi.org/10.1242/dev.07798 2 · DOI
  37. Ray PF, Toure A, Metzler-Guillemain C et al (2017) Genetic abnormal- ities leading to qualitative defects of sperm morphology or func- tion: genetic abnormalities leading to qualitative sperm defects. Clin Genet 91:217-232. https ://doi.org/10.1111/cge.12905 · DOI · Paper page
  38. Shang Y-L, Zhu F-X, Yan J et al (2019) Novel DPY19L2 variants in globozoospermic patients and the overcoming this male infertility. Asian J Androl 21:183-189. https ://doi.org/10.4103/aja.aja_79_18 · DOI · Paper page
  39. Tokuhiro K, Isotani A, Yokota S et al (2009) OAZ-t/OAZ3 is essential for rigid connection of sperm tails to heads in mouse. PLoS Genet 5:e1000712. https ://doi.org/10.1371/journ al.pgen.10007 12 · DOI
  40. Touré A, Martinez G, Kherraf Z-E et al (2020) The genetic architecture of morphological abnormalities of the sperm tail. Hum Genet. https ://doi.org/10.1007/s0043 9-020-02113 -x · DOI
  41. Yatsenko AN, O'Neil DS, Roy A et al (2012) Association of mutations in the zona pellucida binding protein 1 (ZPBP1) gene with abnor- mal sperm head morphology in infertile men. Mol Hum Reprod 18:14-21. https ://doi.org/10.1093/moleh r/gar05 7 · DOI
  42. Zhang J, Wang Y, Zhou Y et al (2005) Yeast two-hybrid screens imply that GGNBP1, GGNBP2 and OAZ3 are potential interaction part- ners of testicular germ cell-specific protein GGN1. FEBS Lett 579:559-566. https ://doi.org/10.1016/j.febsl et.2004.10.112 · DOI
  43. Zhou Y, Zhao Q, Bishop CE et al (2005) Identification and charac- terization of a novel testicular germ cell-specific geneGgnbp1. Mol Reprod Dev 70:301-307. https ://doi.org/10.1002/mrd.20214 · DOI
  44. Zhu F, Gong F, Lin G, Lu G (2013) DPY19L2 gene mutations are a major cause of globozoospermia: identification of three novel point mutations. Mol Hum Reprod 19:395-404. https ://doi. org/10.1093/moleh r/gat01 8 1 3 Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université Montpelier, Montpellier, France 21 CHU de Grenoble, UF de Biologie de la Procréation, 38000 Grenoble, France 22 Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Rennes, France 23 Service de Médecine de la Reproduction, CHU de Saint-Étienne, Hôpital Nord, 42055 Saint-Étienne Cedex 2, France 24 Department of Obstetrics and Gynecology, Hôpital Foch, Université de Paris Ouest (UVSQ), Suresnes, France 25 Service de Biologie de la Reproduction-CECOS, Hôpital Tenon, AP-HP, 75020 Paris, France 26 Department of Obstetrics, Gynaecology and Reproductive Medicine, Picardie University Jules Verne, Amiens University Medical Centre, Amiens, France 27 CHU, Centre d'AMP-CECOS, University Rennes, 16 Boulevard de Bulgarie, 35000 Rennes, France 28 CHU Bretonneau, Médecine et Biologie de la Reproduction-CECOS, Tours, France 29 EA 4308, Department of Reproductive Biology and Spermiology-CECOS Lille, University Medical Center, 59037 Lille, France 30 · DOI

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Authors
Celse, T., Cazin, C., Mietton, F., Martinez, G., Martinez, D., Thierry-Mieg, N., Septier, A., Guillemain, C., Beurois, J., Clergeau, A., Mustapha, S. F. B., Kharouf, M., Zoghmar, A., Chargui, A., Papaxanthos, A., Dorphin, B., Foliguet, B., Triki, C., Sifer, C., Lauton, D., Tachdjian, G., Schuler, G., Lejeune, H., Puechberty, J., Bessonnat, J., Pasquier, L., Mery, L., Poulain, M., Chaabouni, M., Sermondade, N., Cabry, R., Benbouhadja, S., Veau, S., Frapsauce, C., Mitchell, V., Achard, V., Satre, V., Hennebicq, S., Zouari, R., Arnoult, C., Kherraf, Z.-E., Coutton, C., & Ray, P. F.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Centre Hospitalier Universitaire de Grenoble (FR)
  • Centre Hospitalier Universitaire de Caen Normandie (FR)
  • Sorbonne Paris Cité (FR)
  • Hôpital Jean-Verdier (FR)
  • Centre Hospitalier Universitaire de Montpellier (FR)
  • Inserm (FR)
  • Hospices Civils de Lyon (FR)
  • Hôpital Arnaud de Villeneuve (FR)
  • Centre Hospitalier Universitaire de Rennes (FR)
  • Centre Hospitalier Universitaire de Saint-Étienne (FR)
  • Université de Versailles Saint-Quentin-en-Yvelines (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Université de Picardie Jules Verne (FR)
  • Hôpital Bretonneau (FR)
  • Assistance Publique Hôpitaux de Marseille (FR)
Corresponding author
Ray, Pierre F.
ORCID
Venue
Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2020-10-27
Volume
140
Issue
1
Pages
43-57
ISSN
  • 0018-7348 (ISSN-L)
  • 0340-6717
  • 1432-1203
DOI
10.1007/s00439-020-02229-0
OpenAlex
W3095882069
Cited by
42
References
2
Citations by year
2026: 2 · 2025: 9 · 2024: 6 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 2
FWCI
5.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Genetics (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
Agence Nationale de la Recherche (FLAGEL_OME)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
globozoospermia, DPY19L2, male infertility, homozygous deletion, single nucleotide variants, genotype-phenotype correlation, diagnostic approach, candidate genes, truncating mutations
MeSH terms
Teratozoospermia, Exome Sequencing, Genetic Testing, Homozygote, Humans, Infertility, Male, Male, Membrane Proteins, Mutation, Spermatozoa, Testicular Hormones, Cohort Studies, Gene Deletion, Polymorphism, Single Nucleotide, Genetic Association Studies

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