Kuppa Annapurna, Sergeev Yuri V
Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, United States.
J Anal Pharm Res. 2021;10(1):41-48. doi: 10.15406/japlr.2021.10.00364. Epub 2021 Mar 4.
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.
1B型Usher综合征（USH1B）是一种由非常规肌球蛋白VIIa（MYO7A）蛋白突变引起的遗传性疾病。USH1B的特征是内耳异常导致听力丧失，以及色素性视网膜炎导致视力丧失。在此，我们展示了使用同源建模构建并在水中进行5纳秒分子动力学优化的人类MYO7A同二聚体模型。应用全局计算诱变来评估错义突变对遗传性眼病中MYO7A蛋白质结构和稳定性维持的关键作用。我们发现，43.26%（HGMD中178个中的77个）和41.9%（ClinVar中528个中的221个）与疾病相关的错义突变与更高的蛋白质结构破坏效应相关。总体而言，大多数使MYO7A蛋白不稳定的突变与USH1和USH1B相关。特别是，运动结构域和MyTH4结构域被发现最易受导致USH1B表型的突变影响。我们的工作有助于从蛋白质结构的原子水平以及分析基因突变对人类疾病中蛋白质稳定性和基因型与表型关系的影响来理解遗传性疾病。
