Frequency and distribution of NF2 mutations in schwannomas

✍ Scribed by Lee B. Jacoby; Mia MacCollin; Rosemary Barone; Vijaya Ramesh; James F. Gusella

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 832 KB
• Volume: 17
• Category: Article
• ISSN: 1045-2257
• DOI: 10.1002/(sici)1098-2264(199609)17:1<45::aid-gcc7>3.0.co;2-2

✦ Synopsis

Sporadic and inherited schwannomas were scanned for the nature, frequency, and distribution of mutations in the NF2 locus encoding the merlin tumor suppressor protein on 22q. Of 58 tumors, 47% displayed loss of heterozygosity for NFZ, leaving a total of 89 NF2 alleles t o be examined. Pathogenic alterations were identified in 62 of these alleles, including 36 frameshifts with premature termination, I 4 nonsense mutations, and I 2 changes presumed t o affect splicing. Effects of ten of the latter were confirmed in the NFZ transcript and indicated that activation of cryptic splice sites in coding sequence is another frequent mechanism leading t o truncation of merlin. The mutations were relatively evenly distributed across both the protein 4. I superfamily (exons 1-9) and the a-helical (exons 10-1 5) domains of merlin, but they did not occur at all in exons I 6 and 17, which encode the protein's alternative COOH-termini. The data support the "two-hit'' tumor suppressor model for formation of schwannomas and indicate that loss of merlin function can be achieved by truncation at various locations in the protein.

However, the absence of mutations in exons I 6 and I7 suggests that an inactivating mutation affecting only one of the merlin's alternative termini may not be sufficient t o eliminate tumor suppressor function. Genes Chromosom Cancer I7:45-55 (1996).