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Human Molecular Genetics Advance Access published online on July 1, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg219
© 2003 by Oxford University Press
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©2003 Oxford University Press

Article

Targeted disruption of exons 1 to 6 of the Fanconi Anemia group A gene leads to growth retardation, strain-specific microphthalmia, meiotic defects and primordial germ cell hypoplasia

Jasmine C.Y. Wong 1*, Noa Alon 2, Colin Mckerlie 3, Jun R. Huang 2, M. Stephen Meyn 4, and Manuel Buchwald 1

1 Program in Genetics and Genomics Biology, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
2 Program in Genetics and Genomics Biology, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada
3 Integrative Biology Program, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 1L5.
4 Program in Genetics and Genomics Biology, Research Institute, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario M5S 1A8

* To whom correspondence should be addressed. E-mail: jcywong{at}sickkids.ca.


  Abstract

Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents. Recent studies suggest that FA proteins share a common pathway with BRCA proteins. To study the in vivo role of the Fanconi Anemia group A gene (Fanca), gene-targeting techniques were used to generate Fancatm1Hsc mice in which Fanca exons 1 to 6 were replaced by a {beta}-galactosidase reporter construct. Fancatm1.1Hsc mice were generated by Cre-mediated removal of the neomycin cassette in Fancatm1Hsc mice. Fancatm1.1Hsc homozygotes display FA-like phenotypes including growth retardation, microphthalmia and craniofacial malformations that are not found in other Fanca mouse models, and the genetic background affects manifestation of certain phenotypes. Both male and female mice homozygous for Fanca mutation exhibit hypogonadism, and homozygous females demonstrate premature reproductive senescence and an increased incidence of ovarian cysts. We showed that fertility defects in Fancatm1.1Hsc homozygotes might be related to a diminished population of primordial germ cells (PGCs) during migration into the gonadal ridges. We also found a high level of Fanca expression in pachytene spermatocytes. Fancatm1Hsc homozygous males exhibited an elevated frequency of mispaired meiotic chromosomes and increased apoptosis in germ cells, implicating a role for Fanca in meiotic recombination. However, the localization of Rad51, Brca1, Fancd2 and Mlh1 appeared normal on Fancatm1Hsc homozygous meiotic chromosomes. Taken together, our results suggest that the FA pathway plays a role in the maintenance of reproductive germ cells and in meiotic recombination.


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