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

Abstract

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.

• Authors: Thomas E Heineman, D Gareth R Evans, Fabien Campagne, Samuel H Selesnick
• Journal: Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology (Otol Neurotol) Vol. 36 Issue 5 Pg. 908-14 (Jun 2015) ISSN: 1537-4505 [Electronic] United States
• PMID: 25931164 (Publication Type: Journal Article)

Topics

• 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