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Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia

Nature Genetics volume 12, pages 448–451 (1996)Cite this article

Abstract

Fanconi anaemia (FA) is an autosomal recessive disease characterized by bone marrow failure, variable congenital malformations and predisposition to malignancies1,2. Cells derived from FA patients show elevated levels of chromosomal breakage and an increased sensitivity to bifunctional alkylating agents such as mitomycin C (MMC) and diepoxybutane (DEB)3,4. Five complementation groups have been identified by somatic cell methods5,6, and we have cloned the gene defective in group C (FAC)7. To understand the in vivo role of this gene, we have disrupted murine Fac and generated mice homozygous for the targeted allele. The −/− mice did not exhibit developmental abnormalities nor haematologic defects up to 9 months of age. However, their spleen cells had dramatically increased numbers of chromosomal aberrations in response to MMC and DEB. Homozygous male and female mice also had compromised gametogenesis, leading to markedly impaired fertility, a characteristic of FA patients2. Thus, inactivation of Fac replicates some of the features of the human disease.

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Authors and Affiliations

  1. Research Institute, Department of Genetics, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada

    Ming Chen, Wojtek Auerbach, Colin McKerlie, Lili Liu, Olga Gan, Madeleine Carreau, Tim Groves, Cynthia J. Guidos, Melvin H. Freedman, John E. Dick & Manuel Buchwald

  2. McMaster University, Hamilton, Ontario, Canada

    Darrell J. Tomkins

  3. Skirball Institute of Biomolecular Medicine, New York University, New York, New York, USA

    Wojtek Auerbach, Anna Auerbach & Alexandra L. Joyner

  4. Department of Pathology, Ontario Veterinary College, Guelph, Ontario, Canada

    Colin McKerlie & Dean H. Percy

  5. Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Hagop Youssoufian

  6. Department of Immunology, University of Toronto, Ontario, Canada

    Cynthia J. Guidos

  7. Department of Pediatrics, University of Toronto, Ontario, Canada

    Melvin H. Freedman

  8. Mount Sinai Hospital, Toronto, Ontario, Canada

    Jay Cross

  9. Department of Molecular and Medical Genetics, University of Toronto, Ontario, Canada

    Jay Cross, John E. Dick & Manuel Buchwald

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Chen, M., Tomkins, D., Auerbach, W. et al. Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia. Nat Genet 12, 448–451 (1996). https://doi.org/10.1038/ng0496-448

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