A truncating MEIOB mutation responsible for familial primary ovarian insufficiency abolishes its interaction with its partner SPATA22 and their recruitment to DNA double-strand breaksResearch in context
Sandrine Caburet,
Anne-Laure Todeschini,
Cynthia Petrillo,
Emmanuelle Martini,
Nada D. Farran,
Bérangère Legois,
Gabriel Livera,
Johnny S. Younis,
Stavit Shalev,
Reiner A. Veitia
Affiliations
Sandrine Caburet
Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France; Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France
Anne-Laure Todeschini
Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France; Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France
Cynthia Petrillo
Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France; UMR1274, Genetic Stability Stem Cells and Radiation, CEA/DRF/iRCM/SCSR/LDG, Fontenay aux Roses F-92265, France; Université Paris-Sud, Paris, Saclay, France
Emmanuelle Martini
Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France; UMR1274, Genetic Stability Stem Cells and Radiation, CEA/DRF/iRCM/SCSR/LDG, Fontenay aux Roses F-92265, France; Université Paris-Sud, Paris, Saclay, France
Nada D. Farran
OBGYN Department, Genetic Institute, Haemek Medical Center, Afula, Israel
Bérangère Legois
Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France; Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France
Gabriel Livera
Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France; UMR1274, Genetic Stability Stem Cells and Radiation, CEA/DRF/iRCM/SCSR/LDG, Fontenay aux Roses F-92265, France; Université Paris-Sud, Paris, Saclay, France
Johnny S. Younis
Baruch Padeh Medical Center, Poriya, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; Corresponding authors at: J. S Younis, Baruch Padeh Medical Center, Poriya, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; R.A. Veitia, Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France
Stavit Shalev
OBGYN Department, Genetic Institute, Haemek Medical Center, Afula, Israel; Genetic Institute, Emek Medical Center, Israel
Reiner A. Veitia
Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France; Université Paris Diderot-Paris 7, 75205 Paris Cedex 13, France; Corresponding authors at: J. S Younis, Baruch Padeh Medical Center, Poriya, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel; R.A. Veitia, Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France
Background: Primary Ovarian Insufficiency (POI), a major cause of infertility, affects about 1–3% of women under forty years of age. Although there is a growing list of causal genetic alterations, POI remains mostly idiopathic. Methods: We performed exome sequencing (WES) of two sisters affected with POI, one unaffected sister and their mother from a consanguineous family. We assessed the impact of the identified MEIOB variant with a minigene assay and by sequencing illegitimate transcripts from the proband's leukocytes. We studied its functional impact on the interaction between MEIOB with its partner SPATA22 and their localization to DNA double-strand breaks (DSB). Findings: We identified a homozygous variant in the last base of exon 12 of MEIOB, which encodes a factor essential for meiotic recombination. This variant was predicted to strongly affect MEIOB pre-mRNA splicing. Consistently, a minigene assay showed that the variant induced exon 12 skipping, which was confirmed in vivo in the proband's leukocytes. Aberrant splicing leads to the production of a C-terminally truncated protein that cannot interact with SPATA22, abolishing their recruitment to DSBs. Interpretation: This truncating MEIOB variant is expected to provoke meiotic defects and a depleted follicular stock, as in Meiob−/− mice. This is the first molecular defect reported in a meiosis-specific single-stranded DNA-binding protein (SSB) responsible for POI. We hypothesise that alterations in other SSB proteins could explain cases of syndromic or isolated ovarian insufficiency. Fund: Université Paris Diderot, Fondation pour la Recherche Médicale, Fondation ARC contre le cancer, Commissariat à l'Energie Atomique and Institut Universitaire de France. Keywords: Exon skipping, Female infertility, MEIOB, Meiotic recombination, Primary ovarian insufficiency
