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.