International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 143 - LOSS OF P53 SENSITIZES MICE WITH A MUTATION IN CCM1 (KRIT1) TO DEVELOPMENT OF VASCULAR MALFORMATIONS

Plummer NW 1, Gallione CJ 2, Srinivasan S 2, Louis DN 3, Marchuk DA 2

1 National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States, 2 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States, 3 Department of Pathology, Neurosurgical Service and Cancer Center, Massachussets General Hospital and Harvard University, Boston, MA, United States

Cerebral cavernous malformations (CCM) consist of clusters of abnormally dilated blood vessels within the central nervous system.  Hemorrhaging of these lesions can result in headaches, seizures, and lethal stroke.  Three loci are associated with autosomal dominant CCM, and the causative genes have been identified for CCM1 and CCM2.  The allelic series for both genes suggests that disease results from loss of protein function, and it has been proposed that growth of cavernous malformations depends on somatic mutation of the wild-type allele in heterozygotes.  To test this hypothesis, we bred mice that were heterozygous for a targeted mutation of Ccm1 and homozygous for loss of the tumor suppressor Trp53 (p53) which has been reported to increase the rate of somatic mutation due to mitotic recombination, interstitial deletion, and whole chromosome loss and reduplication.  We observed vascular lesions in the brains of 5/9 of the Ccm1+/- Trp53-/- animals but none in littermates of other genotypes.  Histologic and immunohistochemical analyses revealed that the mouse lesions shared distinctive characteristics with human cavernous malformations.  Although the genetic evidence suggested somatic mutation of Ccm1, laser capture microdissection of a mouse lesion failed to reveal loss of heterozygosity.  An alternative explanation for these results is that p53 plays a direct role in formation of the vascular lesions.  The striking similarity of the human and mouse lesions indicates that the Ccm1+/- Trp53-/- mice are an appropriate animal model of cerebral cavernous malformations.

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