EXON SCANNING FOR MUTATION OF THE NF2 GENE IN SCHWANNOMAS

Family studies and tumor analyses have combined to indicate that neuro fibromatosis 2 (NF2), a disorder characterized by multiple benign tumo rs of the nervous system, and sporadic non-inherited forms of the same tumor types are both caused by inactivation of a tumor suppressor gen e located in 22q12. Recently, the gene encoding merlin, a novel member of a family of cytoskeleton-associated proteins, was identified as th e NF2 tumor suppressor. To facilitate the search for merlin mutations, we have defined the exon - intron boundaries for all 17 NF2 exons, in cluding one subject to alternative splicing. We have developed polymer ase chain reaction assays to amplify each exon from genomic DNA, and u sed these assays to perform single-strand conformation polymorphism an alysis of DNA from 30 sporadic and eight NF2-derived schwannomas, the hallmark tumor type in this disorder. Of a maximum of 60 alleles scann ed, 32 showed mutations affecting expression of the merlin protein. Th irty of these mutations are predicted to lead to a truncated protein d ue to frameshift, creation of a stop codon, or interference with norma l splicing, while two are missense mutations. Thus, inactivation of me rlin is a common feature underlying both inherited and sporadic forms of schwannoma.