Neurofibromatosis and associated tumour suppressor genes.

Neurofibromatosis 1 and 2 (NF1 and NF2) are autosomal dominantly inherited disorders with close to 100% penetrance. NF1 is one of the most frequent human genetic diseases with an incidence of 1:3000. The incidence of NF2 is about 10 fold lower. NF1 is caused by mutations which inactivate the NF1 gene on chromosome 17q, while the NF2 gene is on chromsome 22. Both genes are tumour suppressor genes. The product of the NF1 gene, called neurofibromin, is a large protein of 2818 amino acids. The protein acts as a negative regulator in the ras signal transduction pathway and may also act downstream of ras. In the cell types that are affected in NF1 patients, the absence of neurofibromin leads to increased proliferation resulting in benign, and in some cases malignant tumours. The product of the NF2 gene is a protein of 595 amino acids. The protein displays in its N-terminal half considerable homology with proteins that are involved in contacts between the cytoskeleton and the cell membrane, and a similar function has been proposed for the NF2 protein. How the absence of the NF2 protein may lead to the development of Schwannomas and meningiomas, which are the major manifestations of NF2 in patients, is not clear at present.