IDENTIFICATION AND CHARACTERIZATION OF NF1-RELATED LOCI ON HUMAN-CHROMOSOME-22, HUMAN-CHROMOSOME-14 AND HUMAN-CHROMOSOME-2

Neurofibromatosis type 1 (NF1) is a frequent hereditary disorder. The disease is characterized by a very high mutation rate (up to 1/10000 g ametes per generation). NF1-related loci in the human genome have been implicated in the high mutation rate by hypothesizing that these carr y disease-causing mutations, which can be transferred to the functiona l NF1 gene on chromosome arm 17q by interchromosomal gene conversion. To test this hypothesis, we want to identify and characterize the NF1- related loci in the human genome. In this study, we have localized an NF1-related locus in the most centromeric region of the long arm of ch romosome 22. We demonstrate that this locus contains sequences homolog ous to cDNAs that include the GAP-related domain of the functional NF1 gene. However, the GAP-related domain itself is not represented in th is locus. In addition, cosmids specific to this locus reveal, by in si tu hybridization, NF1-related loci in the pericentromeric region of ch romosome arm 14q and in chromosomal band 2q21. These cosmids will enab le us to determine whether identified disease-causing mutations are pr esent at the chromosome 22-associated NF1-related locus.