Neurofibromatosis (NF) is a common human autosomal dominant condition characterized by cafe-au-lait spots, neurofibromas, and a broad range of other manifestations. Its high spontaneous mutation rate (among the highest described in man) and preliminary linkage analysis using protein polymorphisms has suggested that the responsible mutation may be at a different locus in different families. The power of linkage analysis to identify the location of a mutant gene has recently been greatly extended by the introduction of DNA polymorphisms as genetic markers, which should allow any disease gene to be mapped if appropriate families are available for study, and if a sufficient number of informative markers can be generated. NF is a highly appropriate target disorder for this approach. We propose to ascertain three or four three-generation families with NF and sufficient available family members to allow linkage analysi on single families, so that potential locus heterogeneity will not destroy any associations. Using EB virus transformed lymphocytes, we will look for evidence of linkage to GC blood group (chr. 4) and secretor (chr. 19) both of which have been suggested to show linkage to NF in some but not all families. We will also develop and study markers on chromosome 8 (where circumstantial evidence suggests the NF locus might be, and for which DNA probes are needed anyway). We will maximize the rapidity of obtaining linkage information on other autosomal chromosomes by using probes for multigene families, as well as the """"""""minisatellite"""""""" probes recently described which detect a large family of polymorphic markers on a single Southern blot.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023410-02
Application #
3406849
Study Section
Neurology C Study Section (NEUC)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gutmann, D H; Cole, J L; Collins, F S (1995) Expression of the neurofibromatosis type 1 (NF1) gene during mouse embryonic development. Prog Brain Res 105:327-35
Legius, E; Hall, B K; Wallace, M R et al. (1994) Ten base pair duplication in exon 38 of the NF1 gene. Hum Mol Genet 3:829-30
Gutmann, D H; Cole, J L; Stone, W J et al. (1994) Loss of neurofibromin in adrenal gland tumors from patients with neurofibromatosis type I. Genes Chromosomes Cancer 10:55-8
Hajra, A; Martin-Gallardo, A; Tarle, S A et al. (1994) DNA sequences in the promoter region of the NF1 gene are highly conserved between human and mouse. Genomics 21:649-52
Legius, E; Marchuk, D A; Collins, F S et al. (1993) Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet 3:122-6
Andersen, L B; Fountain, J W; Gutmann, D H et al. (1993) Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nat Genet 3:118-21
Colman, S D; Collins, F S; Wallace, M R (1993) Characterization of a single base-pair deletion in neurofibromatosis type 1. Hum Mol Genet 2:1709-11
Gutmann, D H; Boguski, M; Marchuk, D et al. (1993) Analysis of the neurofibromatosis type 1 (NF1) GAP-related domain by site-directed mutagenesis. Oncogene 8:761-9
Andersen, L B; Tarle, S A; Marchuk, D A et al. (1993) A compound nucleotide repeat in the neurofibromatosis (NF1) gene. Hum Mol Genet 2:1083
Gutmann, D H; Collins, F S (1993) Neurofibromatosis type 1. Beyond positional cloning. Arch Neurol 50:1185-93

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