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Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa

Authors :
Cazin, Caroline
Boumerdassi, Yasmine
Martinez, Guillaume
Fourati Ben Mustapha, Selima
Whitfield, Marjorie
Coutton, Charles
Thierry-Mieg, Nicolas
Di Pizio, Pierre
Rives, Nathalie
Arnoult, Christophe
Touré, Aminata
Ray, Pierre
Zouari, Raoudha
Sifer, Christophe
Kherraf, Zine-Eddine
Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB)
Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)
Hôpital Jean Verdier [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Centre Hospitalier Universitaire [Grenoble] (CHU)
Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR)
Clinique de Promotion des Sciences de la Reproduction
Institut Cochin (IC UM3 (UMR 8104 / U1016))
Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Biologie Computationnelle et Modélisation (TIMC-BCM )
Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC )
VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )
Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )
Université Grenoble Alpes (UGA)
Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG)
Université de Rouen Normandie (UNIROUEN)
Normandie Université (NU)-Normandie Université (NU)-Université de Lille
Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501)
Université de Tours
Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR)
Polyclinique les Jasmins [Tunis]
Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Université de Tours (UT)
ANR-17-CE13-0023,DIVERCIL,Analyse de la diversité des cils et des flagelles(2017)
ANR-19-CE17-0014,FLAGEL-OME,Aspects fondamentaux, génétiques et cliniques de l'infertilité masculine causée par des anomalies sévères des flagelles spermatiques(2019)
Thierry-Mieg, Nicolas
Source :
International Journal of Molecular Sciences, International Journal of Molecular Sciences, MDPI, 2021, 22 (4), pp.2187. ⟨10.3390/ijms22042187⟩, International Journal of Molecular Sciences, 2021, 22 (4), pp.2187. ⟨10.3390/ijms22042187⟩, International Journal of Molecular Sciences, Vol 22, Iss 2187, p 2187 (2021), Volume 22, Issue 4
Publication Year :
2021
Publisher :
HAL CCSD, 2021.

Abstract

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.

Details

Language :
English
ISSN :
16616596 and 14220067
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences, International Journal of Molecular Sciences, MDPI, 2021, 22 (4), pp.2187. ⟨10.3390/ijms22042187⟩, International Journal of Molecular Sciences, 2021, 22 (4), pp.2187. ⟨10.3390/ijms22042187⟩, International Journal of Molecular Sciences, Vol 22, Iss 2187, p 2187 (2021), Volume 22, Issue 4
Accession number :
edsair.pmid.dedup....24d6f3428461083abcc05391999a7577
Full Text :
https://doi.org/10.3390/ijms22042187⟩