A splice donor variant of GAS8 induces structural disorganization of the axoneme in sperm flagella and leads to nonsyndromic male infertility.

Autor: Kherraf ZE; Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France.; CHU Grenoble Alpes, UM GI-DPI, Grenoble, France., Barbotin AL; CHU Lille, Institut de Biologie de la Reproduction-Spermiologie-CECOS, Lille, France., Martinez G; Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France.; CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France., Mazet A; Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France., Cazin C; Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France.; CHU Grenoble Alpes, UM GI-DPI, Grenoble, France., Coutton C; Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France.; CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France., Arnoult C; Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France., Thierry-Mieg N; Univ. Grenoble Alpes, CNRS, UMR 5525, TIMC/MAGe, Grenoble, France., Rives N; Team Adrenal and Gonadal Pathophysiology, Inserm, U1239 NorDIC, University Rouen Normandie, Rouen, France.; Reproductive Biology Laboratory-CECOS, Rouen University Hospital, Rouen, France., Rives-Feraille A; Team Adrenal and Gonadal Pathophysiology, Inserm, U1239 NorDIC, University Rouen Normandie, Rouen, France.; Reproductive Biology Laboratory-CECOS, Rouen University Hospital, Rouen, France., Ray PF; Team Genetics Epigenetics and Therapies of Infertility (GETI), Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Univ. Grenoble Alpes, Grenoble, France.; CHU Grenoble Alpes, UM GI-DPI, Grenoble, France.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2024 Feb; Vol. 105 (2), pp. 220-225. Date of Electronic Publication: 2023 Nov 11.
DOI: 10.1111/cge.14450
Abstrakt: 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.
(© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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