Pathogenesis of Germline and Somatic NF1 Gene Rearrangements
Abstract
We have identified novel rearrangements of the NF1 gene in germline and somatic tissues of patients with neurofibromatosis type 1. Germline microdeletions are caused by recombination between repeated elements flanking the NF1 gene. Our data provide strong support for a novel gene within 1 Mb of NF1 that potentiates neurofibromagenesis. Our clinical and molecular analyses of NF1 deletion patients suggest that at least some NF1 microdeletions may be predictive for an early age at onset and heavy burden of cutaneous neurofibromas. We identified a patient who is mosaic for an NF1 microdeletion, which proves that these rearrangements can occur in somatic tissues and that mosaicism may be more prevalent than expected. We have identified novel somatic rearrangements in leukemic cells of NF1 children that arise by double mitotic recombination with clustered breakpoints. Because both the germline and somatic rearrangements involve not only the NF1 gene but many other contiguous genes, our data implicate other elements/loci that play an important role in sporadic cases of NF1 and in somatic inactivation of NF1 during leukemogenesis and possibly during other NFl-associated neoplasms. In addition, these results have direct implications for rationale design of putative therapies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2000
- Accession Number
- ADA387943
Entities
People
- Karen Stephens
Organizations
- University of Washington