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Frequency and distribution of NF2 mutations in schwannomas
L B Jacoby1, M MacCollin, R Barone
1Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown 02129, USA.
Abstract:
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 NF2, leaving a total of 89 NF2 alleles to be examined. Pathogenic alterations were identified in 62 of these alleles, including 36 frameshifts with premature termination, 14 nonsense mutations, and 12 changes presumed to affect splicing. Effects of ten of the latter were confirmed in the NF2 transcript and indicated that activation of cryptic splice sites in coding sequence is another frequent mechanism 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 not occur at all in exons 16 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 16 and 17 suggests that an inactivating mutation affecting only one of the merlin's alternative termini may not be sufficient to eliminate tumor suppressor function.
Insights
Mutations in the NF2 gene, which encodes the merlin tumor suppressor protein, are common in schwannomas. These genetic alterations, including frameshifts and splicing changes, disrupt merlin function and contribute to tumor development.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Schwannomas are tumors arising from Schwann cells, often associated with the NF2 gene.
- The NF2 gene encodes the merlin protein, a crucial tumor suppressor.
Purpose of the Study:
- To investigate the nature, frequency, and distribution of mutations within the NF2 gene locus in sporadic and inherited schwannomas.
- To understand the mechanisms by which NF2 mutations lead to merlin protein dysfunction.
Main Methods:
- Analysis of 58 schwannoma tumors for mutations in the NF2 gene.
- Loss of heterozygosity analysis for NF2 alleles.
- Identification and characterization of various pathogenic alterations, including frameshifts, nonsense mutations, and splicing defects.
Main Results:
- 47% of tumors showed loss of heterozygosity for NF2.
- Pathogenic mutations were identified in 62% of examined NF2 alleles.
- Mutations were distributed across major merlin protein domains, with a notable absence in exons encoding alternative C-termini.
Conclusions:
- The findings support the two-hit tumor suppressor model for schwannoma formation.
- Merlin protein function loss can occur through truncation at diverse sites.
- Inactivating mutations solely affecting merlin's alternative C-termini may not be sufficient for tumor suppressor function loss.