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Abstract：
This 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.
Pathogenic 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.
The 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).
The 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.
Pathogenic 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.
The 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).
The 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.
摘要：
■本研究旨在开发一种预测模型，以根据蛋白质二级结构对RPE65介导的遗传性视网膜疾病（IRD）进行分类，并分析中国队列中RPE65错义变异的表型-蛋白质结构相关性。
■从UniProt获得RPE65的致病性或可能致病性错义变体，ClinVar,和HGMD数据库。从蛋白质数据库（PDB）检索RPE65的三维结构，并用Pymol软件进行修改。使用LASSO回归和多变量逻辑回归开发了一种新的预测模型来识别RPE65相关的IRD。收集了21位具有RPE65变体的中国先证者，以分析RPE65错义变体的表型-蛋白质结构相关性。
■研究发现，致病性和群体错义变异均与RPE65的结构特征相关。致病变异与床单相关，β-sheet,股线,β-发夹,Fe2+（铁中心），和活动部位空腔，虽然人口变异与螺旋有关，循环,螺旋,和螺旋-螺旋相互作用。新的预测模型显示了预测RPE65变异的疾病类型的准确性和置信度（AUC=0.7531）。该研究在中国患者中发现了25种错义变异，占总突变的72.4%。RPE65相关IRD的临床特征与氨基酸类型的变化之间存在显着相关性，特别是F8的错义变体(H68Y，P419S）。
■该研究基于RPE65的蛋白质结构开发了一种新的预测模型，并研究了中国队列中RPE65错义变体的表型-蛋白质结构相关性。这些发现为RPE65突变的IRD的精确诊断提供了见解。
■从UniProt获得RPE65的致病性或可能致病性错义变体，ClinVar,和HGMD数据库。从蛋白质数据库（PDB）检索RPE65的三维结构，并用Pymol软件进行修改。使用LASSO回归和多变量逻辑回归开发了一种新的预测模型来识别RPE65相关的IRD。收集了21位具有RPE65变体的中国先证者，以分析RPE65错义变体的表型-蛋白质结构相关性。
■研究发现，致病性和群体错义变异均与RPE65的结构特征相关。致病变异与床单相关，β-sheet,股线,β-发夹,Fe2+（铁中心），和活动部位空腔，虽然人口变异与螺旋有关，循环,螺旋,和螺旋-螺旋相互作用。新的预测模型显示了预测RPE65变异的疾病类型的准确性和置信度（AUC=0.7531）。该研究在中国患者中发现了25种错义变异，占总突变的72.4%。RPE65相关IRD的临床特征与氨基酸类型的变化之间存在显着相关性，特别是F8的错义变体(H68Y，P419S）。
■该研究基于RPE65的蛋白质结构开发了一种新的预测模型，并研究了中国队列中RPE65错义变体的表型-蛋白质结构相关性。这些发现为RPE65突变的IRD的精确诊断提供了见解。
