Homology modeling and global computational mutagenesis of human myosin VIIa
| Autor: | Annapurna Kuppa, Yuri V. Sergeev |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Genetics
molecular modeling MYO7A computational mutagenesis Usher syndrome Genetic disorder Mutagenesis (molecular biology technique) genetic mutations Biology medicine.disease genotype-to-phenotype Article inherited eye disease Protein structure Usher syndrome type 1B atomic structure Myosin VIIa Retinitis pigmentosa otorhinolaryngologic diseases medicine Missense mutation Homology modeling |
| Zdroj: | Journal of analytical & pharmaceutical research |
| ISSN: | 2473-0831 |
| DOI: | 10.15406/japlr.2021.10.00364 |
| Popis: | Usher syndrome type 1B (USH1B) is a genetic disorder caused by mutations in the unconventional Myosin VIIa (MYO7A) protein. USH1B is characterized by hearing loss due to abnormalities in the inner ear and vision loss due to retinitis pigmentosa. Here, we present the model of human MYO7A homodimer, built using homology modeling, and refined using 5 ns molecular dynamics in water. Global computational mutagenesis was applied to evaluate the effect of missense mutations that are critical for maintaining protein structure and stability of MYO7A in inherited eye disease. We found that 43.26% (77 out of 178 in HGMD) and 41.9% (221 out of 528 in ClinVar) of the disease-related missense mutations were associated with higher protein structure destabilizing effects. Overall, most mutations destabilizing the MYO7A protein were found to associate with USH1 and USH1B. Particularly, motor domain and MyTH4 domains were found to be most susceptible to mutations causing the USH1B phenotype. Our work contributes to the understanding of inherited disease from the atomic level of protein structure and analysis of the impact of genetic mutations on protein stability and genotype-to-phenotype relationships in human disease. |
| Databáze: | OpenAIRE |
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