NEUROFIBROMATOSIS--MOLECULAR-GENETIC APPROACH

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Von Recklinghausen-Neurofibromatosis (NF1) is one of the most common autosomal dominant Mendelian disorders affecting man. It is also the most common inherited predisposition toward tumor formation in man. The gene for NF1 has recently been the location further refined by the observation of NF patients with translocations involving chromosome 17. The study of patients with chromosome deletions may greatly aid int he identification of the NF1 gene. These patients are clinically recognized by the occurrence of several inherited conditions in one individual often accompanied by mental retardation. Three such patients have been identified. Two patients are mentally retarded and have a de novo occurrence of NF1 and achondroplasia (ACH). Because the chance association of these two diseases would be approximately 1 in 700 million, this suggests that these two diseases may be caused by a small deletion on chromosome 17. A third mentally retarded patient has NF1 and a cytogenetically visible deletion of chromosome 17. The proposed research has four specific aims directed towards analysis of the NF1 locus: 1) Identification of missing DNA sequences from patient with putative deletions by quantitative Southern blotting and pulsed-field gel electrophoresis using single copy DNA sequences tightly linked to the NF1 locus. 2) Elucidation of possible mechanisms of tumor formation in tumor cell lines established from NF1 benign and malignant tumors by analysis for loss of chromosomal material and loss of heterozygosity. 3) Development of novel techniques for identifying small chromosomal deletions using the analysis of hybrid cell lines containing a single chromosome 17 with interspersed repeated DNA sequences. This strategy could have major implications for the analysis of constitutional or somatic deletions in other diseases, for example NF2. 4) Molecular analysis of the mutation(s) causing Familial Spinal Neurofibromatosis by analysis of two families with autosomal dominant spinal neurofibromas. These families have shown linkage to the NF1 locus in preliminary studies. The sequence analysis of these mutation(s) may uniquely contribute to our understanding of tumorigenesis in NF1. These studies will contribute towards elucidating the molecular basis of NF1 mutations.