Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder that has significant clinical morbidity. The genetic defect in NF1 is not known and little is understood of the underlying pathophysiology leading to the various clinical manifestations. The identification, isolation and characterization of the NF1 gene is paramount for further studies on the pathophysiology of this highly pleiotropic condition. The NF1 gene has been mapped to band q11.2 on chromosome 17 and the NF1 locus has been further defined by mapping two balanced translocations responsible for the NF1 condition. Physical mapping studies have defined breakpoints approximately 60-kb apart, thus physically defining a region likely to encompass the NF1 gene. Cloned, physically mapped genomic DNA encompassing the NF1 locus enables on to identify active transcripts from this region which will be used as probes to search for rearrangements in NF1 patient genomic DNA. A battery of NF1 rearrangements near one specific candidate gene locus would identify the NF1 gene. Providing the NF1 gene is identified, NF1 cDNAs will be sequenced and mapped to the genomic sequence and mutant alleles from NF1 individuals will be characterized at the DNA sequence level. Complementary DNA sequence will be used to characterize expression of the NF1 gene in neural crest-derived tissue. Successful completion of these specific aims will provide reagents for clinical diagnosis and prognosis counseling for NF1 individuals. The characterization of the NF1 gene may also provide insight into the processes of developmentally regulated gene expression in neural crest-derived tissue, and tumor progression in a neoplasia- associated dominant genetic disorder. David Viskochil is a Ph.D., M.D. completing a genetics fellowship training program with Dr. John Carey and Dr. Ray White at the University of Utah. He has devoted 90% of his training effort to mapping the NF1 locus as part of an NF1 research project directed by Ray White and supported by the Howard Hughes Medical Institute. Dr. Viskochil plans to continue working on the isolation and characterization of the NF1 gene after beginning a faculty appointment in the Department of Pediatrics at the University of Utah in July 1990. He will be affiliated with the Division of Human Genetics and he will conduct all research in an integrated fashion with the core NF1 research group supported by the Howard Hughes Medical Institute.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Leppig, K A; Viskochil, D; Neil, S et al. (1996) The detection of contiguous gene deletions at the neurofibromatosis 1 locus with fluorescence in situ hybridization. Cytogenet Cell Genet 72:95-8
Li, Y; O'Connell, P; Breidenbach, H H et al. (1995) Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 25:9-18
Purandare, S M; Huntsman Breidenbach, H; Li, Y et al. (1995) Identification of neurofibromatosis 1 (NF1) homologous loci by direct sequencing, fluorescence in situ hybridization, and PCR amplification of somatic cell hybrids. Genomics 30:476-85
Bleyl, S; Ainsworth, P; Nelson, L et al. (1994) An ancient Ta subclass L1 insertion results in an intragenic polymorphism in an intron of the NF1 gene. Hum Mol Genet 3:517-8