In Silico Analysis of NF2 Gene Missense Mutations in Neurofibromatosis Type 2: From Genotype to Phenotype

Otol Neurotol. 2015 Jun;36(5):908-14. doi: 10.1097/MAO.0000000000000639.


Hypothesis: Computer-based (in silico) protein modeling to examine genotype-phenotype relationships for a given mutation has been applied to many genes but never to NF2.

Background: Missense mutations in the merlin protein occur in approximately 9% of patients with neurofibromatosis type 2 (NF2). Within this subset of patients, no genotype-phenotype correlations have been established. The aim of this study was to determine if genotype correlates with phenotype in the cohort of NF2 patients with missense mutations as a first step to defining a method to predict clinical phenotype from genotype for these patients.

Methods: We analyzed 45 patients with NF2 as a result of missense mutations drawn from the United Kingdom NF2 registry. Our analysis included 17 different NF2 mutations from NF2 patients and six single-nucleotide polymorphisms (SNP)--presumed benign because they are observed in the dbSNP National Center for Biotechnology Information database and 1000 Genomes. We analyzed the mutations using three mutation tolerance prediction approaches: Align GVGD, SIFT, and PolyPhen-2. The mutation sites were also modeled on the three-dimensional crystal structure of merlin to investigate the spatial relationship of NF2-causing mutations.

Results: Two mutation tolerance predictors (SIFT and PolyPhen-2) were able to distinguish NF2-causing mutations from non-NF2-causing SNPs (p < 0.05). Mapping mutations on the molecular structure of merlin suggest that mutations resulting in greater structural conflicts within the protein are more likely to correlate with severe phenotypes.

Conclusion: This work is a step toward a better understanding of genotype-phenotype relationships in NF2 caused by missense mutations using a computer-based methodology.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Computer Simulation*
  • Female
  • Genes, Neurofibromatosis 2*
  • Genetic Association Studies / methods*
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense
  • Neurofibromatosis 2 / genetics*
  • United Kingdom
  • Young Adult