Search for the gene involved in von Recklinghausen neurofibromatosis.

Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder in all human populations and is characterized by pigmented dermal lesions (cafe-au-lait spots) and benign skin tumors (neurofibromas). The mutation rate for NF1 is among the highest known for a human disease (10$\sp{-4}$/allele/generation) and 50% of individuals affected with this disease represent new mutants at the NF1 locus. A number of different avenues of research have been pursued by us in an effort to identify the gene involved in NF1. The first, or candidate gene approach, was based on the assumption that the NF1 gene was an oncogene. Using this approach, a number of preliminary studies were performed in an attempt to identify this gene due to its presumed ability to aid in cellular transformation. These efforts yielded inconclusive results. Fortunately another method, known as reverse genetics, has evolved and been used successfully to locate the NF1 gene. We applied this approach after the locus for NF1 was linked to chromosome 17. We have primarily used physical mapping techniques to further refine the location of the NF1 gene and these analyses were greatly aided by the identification of two NF1 patients who possess constitutional reciprocal translocations involving chromosome 17 with chromosome 1 or 22. The breakpoints on chromosome 17 in these two translocations reside within 17q11.2 and are thought to disrupt the NF1 locus. These two breakpoints, therefore, serve as signposts for the NF1 gene and we have been successful in identifying both of them by the detection of altered high molecular weight DNA fragments on pulsed-field gels. The two breakpoints reside within a relatively small region of 200 kb on chromosome 17 where, in addition, a recently identified murine oncogene, evi-2, has also been mapped. No strong evidence exists at this point in time, however, to support the involvement of the human analog of evi-2 in NF1 and future analyses are aimed at more precisely mapping the region which contains the NF1 locus in an effort to identify the definitive disease gene. This thesis project has aided significantly in the mapping of NF1 and has set the stage for the identification of this disease gene in the very near future.Ph.D.Biological SciencesGeneticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128363/2/9001626.pd