Progress toward the isolation and characterization of the genes causing neurofibromatosis

Neurofibromatosis 1 and neurofibromatosis 2 are clinically distinct autosomal dominant disorders that affect an estimated 1.5 million individuals throughout the world. The genetic defect in each disorder has been mapped to different chromosomes, NF1 to chromosome 17 and NF2 to chromosome 22. Progress towards the cloning of the NF1 gene has proceeded rapidly. The NF1 locus was bracketed using genetic linkage analysis on NF1 affected pedigrees. Physical mapping methods were then used to precisely map the translocation breakpoints in each of two NF1 affected individuals who harbored constitutional chromosomal translocations in the putative NF1 region of chromosome 17. The region of DNA located between the two translocations has been cloned in cosmids and yeast artificial chromosomes and a number of RNA coding sequences have been identified. The identification of the NF1 gene will depend on finding mutations in the DNA of affected individuals. In the case of NF2, progress seems to have been less rapid, in part due to the lower availability of NF2 affected pedigrees. The genetic defect has been mapped to the long arm of chromosome 22 by studies of chromosomal loss in the tumours associated with this disease. Subsequent genetic mapping has confirmed this location. Flanking DNA markers for the NF2 locus have been identified. The region of DNA between these markers is in the order of 5-10 Mb. The identification of chromosomal aberrations in patients with NF2 that involve chromosome 22 will play an important role in the identification of the NF2 gene in much the same way as they have in NF1.