Development of a novel prediction model based on protein structure for identifying RPE65-associated inherited retinal disease (IRDs) of missense variants

PeerJ

article

Jiawen Wu¹  Zhongmou Sun²  Dao wei Zhang¹  Hong-Li Liu¹  Ting Li¹  Shenghai Zhang¹  Jihong Wu¹ 

[1] Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University;University of Rochester School of Medicine and Dentistry;Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality;State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science;Key Laboratory of Myopia, Ministry of Health

关键词: Prediction model;    RPE65;    Leber congenital amaurosis (LCA);    Retinitis pigmentosa(RP);    Inherited retinal disease (IRDs);    Phenotype;    Machine learning;   

DOI  :  10.7717/peerj.15702

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

PurposeThis study aimed to develop a prediction model to classify RPE65-mediated inherited retinal disease (IRDs) based on protein secondary structure and to analyze phenotype-protein structure correlations of RPE65 missense variants in a Chinese cohort.MethodsPathogenic or likely pathogenic missense variants of RPE65 were obtained from UniProt, ClinVar, and HGMD databases. The three-dimensional structure of RPE65 was retrieved from the Protein Data Bank (PDB) and modified with Pymol software. A novel prediction model was developed using LASSO regression and multivariate logistic regression to identify RPE65-associated IRDs. A total of 21 Chinese probands with RPE65 variants were collected to analyze phenotype-protein structure correlations of RPE65 missense variants.ResultsThe study found that both pathogenic and population missense variants were associated with structural features of RPE65. Pathogenic variants were linked to sheet, β-sheet, strands, β-hairpins, Fe2+ (iron center), and active site cavity, while population variants were related to helix, loop, helices, and helix–helix interactions. The novel prediction model showed accuracy and confidence in predicting the disease type of RPE65 variants (AUC = 0.7531). The study identified 25 missense variants in Chinese patients, accounting for 72.4% of total mutations. A significant correlation was observed between clinical characteristics of RPE65-associated IRDs and changes in amino acid type, specifically for missense variants of F8 (H68Y, P419S).ConclusionThe study developed a novel prediction model based on the protein structure of RPE65 and investigated phenotype-protein structure correlations of RPE65 missense variants in a Chinese cohort. The findings provide insights into the precise diagnosis of RPE65-mutated IRDs.

【 授权许可】

CC BY