Defects in neurofibromatosis 2 protein function can arise at multiple levels

Neurofibromatosis 2 (NF2) is an inherited cancer syndrome resulting frommutations in the NF2 tumor suppressor gene. Analysis of NF2 mutations hasrevealed some general genotype-phenotype correlations. Severe disease hasbeen associated with mutations that produce a premature termination whilemore mild disease has been associated with missense mutations. Here, weprovide experimental proof for these genotype-phenotype correlations bydemonstrating that nonsense mutations fail to produce stable merlin proteinwhile missense mutations result in the generation of merlin proteinsdefective in negative growth regulation. This inability to suppress cellgrowth may result from defects in the function of merlin at several levels,including failure to form an intramolecular complex. Based on thesefindings, we propose a model for merlin growth suppression that provides aframework for analyzing NF2 patient mutations and merlin function.