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Publications

Journal Article Ahead of print

PubMed: 42493466 DOI: 10.1111/cge.70220

Biallelic Truncating Variant in LRGUK Is Associated With Severe Multiple Morphological Abnormalities of the Sperm Flagella and Sperm Nuclear Defects in Humans.

Clin Genet

Authors: Wiâme Mokkedem, Zeina Wehbe, Anne-Laure Barbotin, Angèle Boursier, Célia Tebbakh, Nicolas Thierry-Mieg, Marie Bidart, Antonella Migliaccio, Rosanna Chianese, Christophe Arnoult, Raoudha Zouari, Zine-Eddine Kherraf, Pierre F Ray, Guillaume Martinez, Charles Coutton

Affiliations

  • Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, University of Grenoble Alpes, Grenoble, France. CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France.
  • Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, University of Grenoble Alpes, Grenoble, France.
  • CHU Lille, Laboratoire de Biologie de la Reproduction-Spermiologie-CECOS, Lille, France.
  • Development and Plasticity of the Neuroendocrine Brain, University of Lille, Lille, France.
  • CHU Grenoble Alpes, UMGI-DPI, Grenoble, France.
  • CNRS, University of Grenoble Alpes, Grenoble, France.
  • UM Génétique Moléculaire: Maladies Héréditaires et Oncologie, University Hospital Grenoble Alpes, Grenoble, France.
  • Department of Experimental Medicine, University of Campania L. Vanvitelli, Naples, Italy.
  • Polyclinique Les Jasmins, Centre d'Aide Médicale à la Procréation, Tunis, Tunisia.
  • CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France.

Abstract

Multiple morphological abnormalities of the flagella (MMAF) is a severe form of male infertility characterized by immotile spermatozoa with absent, short, coiled, or irregular flagella. Despite advances in whole-exome sequencing, many cases remain genetically unexplained. Here, we identify a homozygous truncating variant in LRGUK (c.1063C>T; p.Arg355Ter) in an infertile man presenting with a typical MMAF phenotype. The variant, identified by whole-exome sequencing in a cohort of 168 MMAF patients and confirmed by Sanger sequencing, is predicted to result in loss of the C-terminal guanylate kinase-like domain. Immunofluorescence showed absence of LRGUK protein in patient spermatozoa, supporting a loss-of-function effect. Semen analysis revealed impaired motility and complete teratozoospermia. Morphological and ultrastructural analyzes demonstrated severe defects affecting both sperm head and flagellum, including disorganized axonemal architecture and central pair abnormalities. Nuclear analyzes showed increased nuclear size, defective chromatin compaction, and elevated DNA fragmentation. Immunostaining further indicated alterations of central apparatus-associated proteins, supporting a role for LRGUK in C1b projection organization. These findings identify LRGUK as a novel gene involved in male infertility, essential for spermatid morphogenesis and flagellum assembly.

MeSH

Genes, Flagella, Infertility, Teratozoospermia, Exome, Infertility, Male, Spermatozoa