Motile cilia and flagella are closely related organelles structured around a highly conserved axoneme whose formation and maintenance involve proteins from hundreds of genes. Defects in many of these genes have been described to induce primary ciliary dyskinesia (PCD) mainly characterized by chronic respiratory infections, situs inversus and/or infertility. In men, cilia/flagella-related infertility is usually caused by asthenozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF). Here, we investigated a cohort of 196 infertile men displaying a typical MMAF phenotype without any other PCD symptoms. Analysis of WES data identified a single case carrying a deleterious homozygous GAS8 variant altering a splice donor consensus site. This gene, also known as DRC4, encodes a subunit of the Nexin-Dynein Regulatory Complex (N-DRC), and has been already associated to male infertility and mild PCD. Confirming the deleterious effect of the candidate variant, GAS8 staining by immunofluorescence did not evidence any signal from the patient's spermatozoa whereas a strong signal was present along the whole flagella length in control cells. Concordant with its role in the N-DRC, transmission electron microscopy evidenced peripheral microtubule doublets misalignments. We confirm here the importance of GAS8 in the N-DRC and observed that its absence induces a typical MMAF phenotype not necessarily accompanied by other PCD symptoms.
Clinical genetics. 2023 Nov 11 [Epub ahead of print]
Zine-Eddine Kherraf, Anne-Laure Barbotin, Guillaume Martinez, Aurélien Mazet, Caroline Cazin, Charles Coutton, Christophe Arnoult, Nicolas Thierry-Mieg, Nathalie Rives, Aurélie Rives-Feraille, Pierre F Ray
Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France., CHU Lille, Institut de Biologie de la Reproduction-Spermiologie-CECOS, Lille, France., Univ. Grenoble Alpes, CNRS, UMR 5525, TIMC/MAGe, Grenoble, France., Team Adrenal and Gonadal Pathophysiology, Inserm, U1239 NorDIC, University Rouen Normandie, Rouen, France.