1. Human Biology and Medicine
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A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

  1. Baptiste Fouquet
  2. Patrycja Pawlikowska
  3. Sandrine Caburet
  4. Celine Guigon
  5. Marika Mäkinen
  6. Laura Tanner
  7. Marja Hietala
  8. Kaja Urbanska
  9. Laura Bellutti
  10. Bérangère Legois
  11. Bettina Bessieres
  12. Alain Gougeon
  13. Alexandra Benachi
  14. Gabriel Livera
  15. Filippo Rosselli
  16. Reiner A Veitia
  17. Micheline Misrahi  Is a corresponding author
  1. Faculté de médecine Paris Sud, France
  2. Université Paris Sud, France
  3. Université Paris Diderot, France
  4. Turku University Hospital, Finland
  5. Hôpital Necker-enfants malades, APHP, France
  6. Faculté de Médecine Laennec, France
Research Article
  • Cited 2
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Cite as: eLife 2017;6:e30490 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 monoubiquitinationFANCM 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.

Article and author information

Author details

  1. Baptiste Fouquet

    Hopital Bicetre, Faculté de médecine Paris Sud, Le Kremlin Bicetre, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Patrycja Pawlikowska

    CNRS UMR8200, Université Paris Sud, Villejuif, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Sandrine Caburet

    Molecular Oncology and Ovarian Pathologies, Institut Jacques Monod, Université Paris Diderot, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-7404-8213
  4. Celine Guigon

    CNRS, UMR 8251, INSERM, U1133, Université Paris Diderot, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Marika Mäkinen

    Department of Clinical Genetics, Turku University Hospital, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  6. Laura Tanner

    Department of Clinical Genetics, Turku University Hospital, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  7. Marja Hietala

    Department of Clinical Genetics, Turku University Hospital, Turku, Finland
    Competing interests
    The authors declare that no competing interests exist.
  8. Kaja Urbanska

    CNRS UMR8200, Université Paris Sud, Villejuif, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Laura Bellutti

    UMR967 INSERM, CEA/DRF/iRCM/SCSR/LDG, Université Paris Diderot, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Bérangère Legois

    Institut Jacques Monod, Université Paris Diderot, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Bettina Bessieres

    Department of Histology, Embryology and Cytogenetics, Hôpital Necker-enfants malades, APHP, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Alain Gougeon

    UMR Inserm 1052, CNRS 5286, Faculté de Médecine Laennec, Lyon, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Alexandra Benachi

    Department of Obstetrics and Gynaecology, Université Paris Sud, Clamart, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Gabriel Livera

    UMR967 INSERM, CEA/DRF/iRCM/SCSR/LDG, Université Paris Diderot, Fontenay aux Roses, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Filippo Rosselli

    CNRS UMR8200, Université Paris Sud, Villejuif, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Reiner A Veitia

    Institut Jacques Monod, Université Paris Diderot, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  17. Micheline Misrahi

    Hopital Bicetre, Faculté de médecine Paris Sud, Le Kremlin Bicetre, France
    For correspondence
    Micheline.misrahi@aphp.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-5379-8859

Funding

Fondation pour la Recherche Médicale (DEQ20150331757)

  • Baptiste Fouquet
  • Sandrine Caburet
  • Reiner A Veitia
  • Micheline Misrahi

Ligue Contre le Cancer

  • Patrycja Pawlikowska
  • Filippo Rosselli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study was approved by all the institutions involved. All participants gave informed consent for the study and the study was approved by the agence de Biomedecine (reference number PFS12-002).

Reviewing Editor

  1. Andrew Deans, St Vincent's Institute of Medical Research, Australia

Publication history

  1. Received: July 18, 2017
  2. Accepted: December 11, 2017
  3. Accepted Manuscript published: December 12, 2017 (version 1)
  4. Version of Record published: January 11, 2018 (version 2)

Copyright

© 2017, Fouquet et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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