Functional analysis of neurofibromatosis 2 (NF2) missense mutations

Neurofibromatosis 2 (NF2) is a tumor predisposition syndrome in which affec ted individuals develop nervous system tumors at an increased frequency. Th e most common tumor in individuals with NF2 is the schwannoma, which is com posed of neoplastic Schwann cells lacking NF2 gene expression. Moreover, in activation of the NF2 gene is observed in nearly all sporadic schwannomas, suggesting that the NF2 gene is a critical growth regulator for Schwann cel ls. In an effort to gain insights into the function of the NF2 gene product , merlin or schwannomin, we performed a detailed functional analysis of eig ht naturally occurring non-conservative missense mutations in the NF2 gene. Using a regulatable expression system in rat schwannoma cells, we analyzed proliferation, actin cytoskeleton-mediated events and merlin folding. In t his report, we demonstrate that mutations clustered in the predicted alpha -helical region did not impair the function of merlin whereas those in eith er the N- or C-terminus of the protein rendered merlin inactive as a negati ve growth regulator. These results suggest that the key functional domains of merlin lie within the highly conserved FERM domain and the unique C-term inus of the protein.