Pathogenesis of Germline and Somatic NF1 Rearrangements
Annual rept. 30 Sep 1997-29 Sep 1998
WASHINGTON UNIV SEATTLE
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We have determined that novel germline and. somatic chromosome rearrangements involving the NFl gene are common in specific subsets of NFl patients. Patients with facial abnormalities and an early age of onset of dermal neurofibromas often carried a germline microdeletion of 1-2 Mb that deleted an NFl allele and flanking DNA. Over 34 of these microdeletions had chromosomal breakpoints hat mapped to the same small interval. These data suggest that microeletions tend to occur at specific sites and they alter the expression of unknown genes that predisposes the patients to early tumor development. Identification of these sites is in progress. In related studies, we determined that leukemic cells of NFl children with malignant myeloid disorders commonly undergo double mitotic recombination events at common breakpoint intervals. This results in a cell without functional NFl alleles and a large interstitial chromosome segment that may be altered in as yet unknown ways. Both of these remarkable rearrangements appear to contribute to tumor development.
- Anatomy and Physiology
- Medicine and Medical Research