Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa
Open accessAbstract
Acephalic spermatozoa syndrome (ASS) is a rare but extremely severe type of teratozoospermia, defined by the presence of a majority of headless flagella and a minority of tail-less sperm heads in the ejaculate. Like the other severe monomorphic teratozoospermias, ASS has a strong genetic basis and is most often caused by bi-allelic variants in SUN5 (Sad1 and UNC84 domain-containing 5). Using whole exome sequencing (WES), we investigated a cohort of nine infertile subjects displaying ASS. These subjects were recruited in three centers located in France and Tunisia, but all originated from North Africa. Sperm from subjects carrying candidate genetic variants were subjected to immunofluorescence analysis and transmission electron microscopy. Moreover, fluorescent in situ hybridization (FISH) was performed on sperm nuclei to assess their chromosomal content. Variant filtering permitted us to identify the same SUN5 homozygous frameshift variant (c.211+1_211+2dup) in 7/9 individuals (78%). SUN5 encodes a protein localized on the posterior part of the nuclear envelope that is necessary for the attachment of the tail to the sperm head. Immunofluorescence assays performed on sperm cells from three mutated subjects revealed a total absence of SUN5, thus demonstrating the deleterious impact of the identified variant on protein expression. Transmission electron microscopy showed a conserved flagellar structure and a slightly decondensed chromatin. FISH did not highlight a higher rate of chromosome aneuploidy in spermatozoa from SUN5 patients compared to controls, indicating that intra-cytoplasmic sperm injection (ICSI) can be proposed for patients carrying the c.211+1_211+2dup variant. These results suggest that the identified SUN5 variant is the main cause of ASS in the North African population. Consequently, a simple and inexpensive genotyping of the 211+1_211+2dup variant could be beneficial for affected men of North African origin before resorting to more exhaustive genetic analyses.
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FISH analysis of sperm aneuploidy in three patients with pinhead spermatozoa syndrome and carrying a SUN5 mutation revealed no increase in aneuploidy rate compared with five fertile controls.
“FISH analysis of sperm aneuploidy in three patients with pinhead spermatozoa syndrome and carrying a SUN5 mutation revealed no increase in aneuploidy rate compared with five fertile controls [54].”
From Recommendations for Human Sperm Morphology Assessment in 2025: An Expert Review From the French BLEFCO Group (2026) · cites this paper as [54]
Mutations of the gene coding for SUN5 protein are the most frequent cause of acephalic sperm syndrome.
“Mutations of the gene coding for the SUN5 protein were the first to be recognised, with more than 10 biallelic variants identified. This is the most frequent cause of acephalic sperm syndrome [54, 55].”
From Recommendations for Human Sperm Morphology Assessment in 2025: An Expert Review From the French BLEFCO Group (2026) · cites this paper as [54]
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- Authors
- Cazin, C., Boumerdassi, Y., Martinez, G., Fourati Ben Mustapha, S., Whitfield, M., Coutton, C., Thierry-Mieg, N., Di Pizio, P., Rives, N., Arnoult, C., Touré, A., Ray, P. F., Zouari, R., Sifer, C., & Kherraf, Z.-E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre d’Aide Médicale à la Procréation, Polyclinique les Jasmin, Centre Urbain Nord, Tunis 1003, Tunisia
- TIMC-IMAG, CNRS, Université Grenoble Alpes, F-38000 Grenoble, France
- EA 4308 ‘Gametogenesis and Gamete Quality, Normandie University, UNIROUEN, F-76000 Rouen, France
- Cecos (FR)
- Corresponding author
- Kherraf, Zine-Eddine
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2021-02-22
- Volume
- 22
- Issue
- 4
- Pages
- 2187
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC7927044
- OpenAlex
- W3132069990
- Cited by
- 16
- References
- 40
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 1 · 2022: 4
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche (ANR-17-CE13-0023, ANR-19-CE17-0014, ANR‐19, ANR-17, CE17-0014)
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- Université Paris Descartes
- 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 › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- acephalic spermatozoa syndrome, teratozoospermia, homozygous frameshift mutation, male infertility, intracytoplasmic sperm injection, North African populations, genotyping
- MeSH terms
- Teratozoospermia, Exome Sequencing, Adult, Africa, Northern, Aneuploidy, Haplotypes, Homozygote, Humans, Male, Membrane Proteins, Middle Aged, Spermatozoa, Genetic Variation, Case-Control Studies, In Situ Hybridization, Fluorescence
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