Neurofibromin in neurofibromatosis type 1 - mutations in NF1gene as a cause of disease.

Neurofibromatosis type I (NF1) is a disease associated with the presence of benign neurofibromas and malignant tumours of the central and peripheral nervous system, that are accompanied by characteristic changes in the skin, such as café-au-lait spots or axillary freckling. In 50% of NF1 patients, the clinical symptoms become apparent below 1st year and in 97%, before the age of 8 years. The disease is mainly caused by the presence of mutation in the NF1 gene that encodes neurofibromin - a protein involved in the regulation of several cellular signaling pathways responsible for cell proliferation and differentiation. Neurofibromin is necessary for embryonic development and involved mainly in the differentiation of neural crest derived cells, mesenchymal cells, neural cells, melanocytes and bone cells. Type I neurofibromatosis is inherited in autosomal dominant manner, nevertheless about 50% of detected mutations are de novo ones. The mutations have full penetrance, although they also have significant pleiotropic effect. Over 1485 different mutations have been identified in the NF1 gene so far, most of which lead to a synthesis of truncated, non-functional protein. It is estimated that the point mutations are responsible for approximately 90% of cases of NF1. The remaining 5-7% of NF1 cases are associated with the presence of a single exon or whole NF1 gene deletion (17q11.2 microdeletion syndrome). The article discusses the role of neurofibromin in cell signaling with the special attention to RAS/MAPK pathway regulation as well as in organism development. Also the basic methods of molecular analysis of NF1 gene are presented in the context of their application in the diagnosis and clinical differentiation of the disease.