Normal neuorfibromin binding maintains Ras in an inactive conformation and prevents it from stimulating cells to grow and divide. When there is a mutation in the NF1 gene, the neurofibromin protein cannot bind to Ras and control its activity. As a result, Ras is constitutively active and multiple pathways are stimulated that direct the cells to divide, forming the tumors seen with this disease.
Other neurofibromin functions have also been identified that may contribute to the pathogenesis of this disease. For example, neurofibromin has been shown to regulate the cyclic adenosine monophosphate (cAMP) pathway, which has been linked to both tumor growth and senescence in NF1. Inability of neurofibromin to regulate this mechanism may be directly related to the development of the neural tumors, independent of the Ras pathway.
A single mutated copy of the NF1 gene is sufficient to result in the clinical syndrome of NF1. However, tumor formation requires loss of function in the second copy of the NF1 gene. More than 500 mutations in the NF1 gene have been identified and it is thought that most of these result in the loss of the normal tumor suppressing function of neurofibromin.
Signals from surrounding cells and disrupted regulation of other genes (modifiers) also play a role in the disease pathogenesis, contributing to the complexity of the clinical symptoms seen in this disorder.