Pathogenesis of Germline and Somatic NF1 Rearrangements
Annual rept. 30 Sep 1998-29 Sep 1999
WASHINGTON UNIV SEATTLE
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We have determined that very unusual chromosomal rearrangements involving the NF1 gene occur in both germline and somatic tissues of certain patients. Germline microdeletions of 1.5 Mb are caused by recombination between repeated elements that flank the NFl gene. Our data support the hypothesis of a co-deletion of NFl and a novel gene that potentiates neurofibromagenesis and narrow the location of this gene. We describe detailed clinical description of 20 NF1 deletion patients, which suggest that NF1 microdeletion may be predictive of phenotype. We have developed an automated PCR-based gene dosage assay to rapidly identify and map the extent of NFl deletions, which should be directly applicable to diagnostic testing of patients. We describe for the first time somatic rearrangements in tumor cells that arise by double mitotic recombination with clustered breakpoints. These rearrangements result in interstitial isodisomy for a 50 Mb region chromosome 17 and occurred in leukemic tumors of children with NP1 and myeloid dysplasia. Because both the germline and somatic rearrangements involve not only the NP1 gene but many other genes, our data implicate other elementsloci that play an important role in sporadic cases of NF1 and in somatic loss of NF1 during leukemogenesis and possibly during other NFl-associated neoplasias.
- Anatomy and Physiology
- Medicine and Medical Research