FREQUENCY AND DISTRIBUTION OF NF2 MUTATIONS IN SCHWANNOMAS

Sporadic and inherited schwannomas were scanned for the nature, freque ncy, and distribution of mutations in the NF2 locus encoding the merli n tumor suppressor protein on 22q. Of 58 tumors, 47% displayed loss of heterozygosity for NF2, leaving a total of 89 NF2 alleles to be exami ned. Pathogenic alterations were identified in 62 of these alleles, in cluding 36 frameshifts with premature termination, 14 nonsense mutatio ns, and 12 changes presumed to affect splicing. Effects of ten of the latter were confirmed in the NF2 transcript and indicated that activat ion of cryptic splice sites in coding sequence is another frequent mec hanism leading to truncation of merlin. The mutations were relatively evenly distributed across both the protein 4.1 superfamily (exons 1-9) and the alpha-helical (exons 10-15) domains of merlin, but they did n or occur at all in exons 16 and 17, which encode the protein's alterna tive COOH-termini. The data support the ''two-hit'' tumor suppressor m odel for formation of schwannomas and indicate that loss of merlin fun ction can be achieved by truncation at various locations in the protei n. However, the absence of mutations in exons 16 and 17 suggests that an inactivating mutation affecting only one of the merlin's alternativ e termini may not be sufficient to eliminate tumor suppressor function . (C) 1996 Wiley-Liss, Inc.