2. Academic Validation
  3. Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP

Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP

  • Hum Mol Genet. 2016 Mar 1;25(5):878-91. doi: 10.1093/hmg/ddv617.
Jessica Escoffier 1,  Hoi Chang Lee 2,  Sandra Yassine 3,  Raoudha Zouari 4,  Guillaume Martinez 3,  Thomas Karaouzène 3,  Charles Coutton 5,  Zine-Eddine Kherraf 3,  Lazhar Halouani 4,  Chema Triki 6,  Serge Nef 1,  Nicolas Thierry-Mieg 7,  Sergey N Savinov 8,  Rafael Fissore 2,  Pierre F Ray 9,  Christophe Arnoult 10
Affiliations

Affiliations

  • 1 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • 2 Department of Veterinary and Animal Sciences and.
  • 3 Université Grenoble Alpes, Grenoble, F-38000, Grenoble, France, Institut Albert Bonniot, INSERM U823, La Tronche F-38700, France.
  • 4 Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003 Tunis, Tunisia.
  • 5 Université Grenoble Alpes, Grenoble, F-38000, Grenoble, France, CHU de Grenoble, UF de Génétique Chromosomique, Grenoble F-38000, France.
  • 6 Clinique Hannibal, Centre d'AMP, les berges du lac, 1053 Tunis, Tunisia.
  • 7 Université Grenoble Alpes, Grenoble, F-38000, Grenoble, France, Laboratoire TIMC-IMAG, UMR CNRS 5525, Grenoble F-38000, France and.
  • 8 Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA.
  • 9 Université Grenoble Alpes, Grenoble, F-38000, Grenoble, France, Institut Albert Bonniot, INSERM U823, La Tronche F-38700, France, CHU de Grenoble, UF de Biochimie et Génétique Moléculaire, Grenoble F-38000, France.
  • 10 Université Grenoble Alpes, Grenoble, F-38000, Grenoble, France, Institut Albert Bonniot, INSERM U823, La Tronche F-38700, France, christophe.arnoult@ujf-grenoble.fr.
PMID: 26721930 DOI: 10.1093/hmg/ddv617
Abstract

In mammals, sperm-oocyte fusion initiates CA(2+) oscillations leading to a series of events called oocyte activation, which is the first stage of embryo development. CA(2+) signaling is elicited by the delivery of an oocyte-activating factor by the sperm. A sperm-specific Phospholipase C (PLCZ1) has emerged as the likely candidate to induce oocyte activation. Recently, PAWP, a sperm-born tryptophan domain-binding protein coded by WBP2NL, was proposed to serve the same purpose. Here, we studied two infertile brothers exhibiting normal sperm morphology but complete fertilization failure after intracytoplasmic sperm injection. Whole exomic Sequencing evidenced a missense homozygous mutation in PLCZ1, c.1465A>T; p.Ile489Phe, converting Ile 489 into Phe. We showed the mutation is deleterious, leading to the absence of the protein in sperm, mislocalization of the protein when injected in mouse GV and MII oocytes, highly abnormal CA(2+) transients and early embryonic arrest. Altogether these alterations are consistent with our patients' sperm inability to induce oocyte activation and initiate embryo development. In contrast, no deleterious variants were identified in WBP2NL and PAWP presented normal expression and localization. Overall we demonstrate in humans, the absence of PLCZ1 alone is sufficient to prevent oocyte activation irrespective of the presence of PAWP. Additionally, it is the first mutation located in the C2 domain of PLCZ1, a domain involved in targeting proteins to cell membranes. This opens the door to structure-function studies to identify the conserved Amino acids of the C2 domain that regulate the targeting of PLCZ1 and its selectivity for its lipid substrate(s).

Figures