A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

  • Elife. 2017 Dec 12;6:e30490. doi: 10.7554/eLife.30490.
Baptiste Fouquet  #  1 ,  Patrycja Pawlikowska  #  2 ,  Sandrine Caburet  3 ,  Celine Guigon  4 ,  Marika Mäkinen  5 ,  Laura Tanner  5 ,  Marja Hietala  5 ,  Kaja Urbanska  6 ,  Laura Bellutti  7 ,  Bérangère Legois  3 ,  Bettina Bessieres  8 ,  Alain Gougeon  9 ,  Alexandra Benachi  10 ,  Gabriel Livera  7 ,  Filippo Rosselli  2 ,  Reiner A Veitia  #  3 ,  Micheline Misrahi  #  1
Affiliations
  • 1. Faculté de Médecine, Université Paris Sud, Université Paris Saclay, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
  • 2. CNRS UMR8200,Equipe labellisée La Ligue Contre Le Cancer, Université Paris Sud, Université Paris Saclay, Gustave Roussy, Vilejuif, France.
  • 3. Institut Jacques Monod, Université Paris Diderot, Paris, France.
  • 4. Université Paris-Diderot, CNRS, UMR 8251, INSERM, U1133, Paris, France.
  • 5. Department of Clinical Genetics, Turku University Hospital, Turku, Finland.
  • 6. CNRS UMR8200, Université Paris Sud, Université Paris Saclay, Villejuif, France.
  • 7. UMR967 INSERM, CEA/DRF/iRCM/SCSR/LDG, Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, Université Paris-Saclay, Fontenay aux Roses, France.
  • 8. Department of Histology, Embryology and Cytogenetics, Hôpital Necker-enfants malades, Paris, France.
  • 9. UMR Inserm 1052, CNRS 5286, Faculté de Médecine Laennec, Lyon, France.
  • 10. Department of Obstetrics and Gynaecology, AP-HP, Université Paris-Sud, Université Paris-Saclay, Clamart, France.
  • # Contributed equally.
PMID: 29231814 DOI: 10.7554/eLife.30490
Abstract

Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome Sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast Cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm-/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.

Keywords
FANCM; Mitomycin C; exome sequencing; human; human biology; medicine; mutation; primary ovarian insufficiency; replication inhibitor.