Molecular Medicine Laboratory, Ege University School of Medicine, Izmir, Turkey.
Department of Pediatric Rheumatology, Faculty of Medicine, Ege University, Izmir, Turkey.
Mol Biol Rep. 2022 Jun;49(6):4643-4652. doi: 10.1007/s11033-022-07312-5. Epub 2022 Mar 16.
OTULIN-related autoinflammatory syndrome (ORAS) is an autosomal recessive disease characterized by systemic inflammation, recurrent fever. Due to limited knowledge about the OTULIN DNA variants that cause ORAS, the diagnosis and treatment of this disease is difficult. In this study, we aim to identify OTULIN DNA variants responsible for the genetic pathology of ORAS and observe the effects of these variants on the OTULIN protein structure and the function with different bioinformatics approaches.
The present study included 3230 individuals with the suspicion of an autoinflammatory disease who were referred to Ege University Children's Hospital Molecular Medicine Laboratory. OTULIN variants were detected using a panel consisting of 37 different autoinflammatory diseases (AID) genes via targeted Next-Generation Sequencing.
As a result of the study, DNA variants associated with various AID were detected in 65% of the individuals to whom the panel was applied. Among these variants, only three different OTULIN variants (p.Val82Ile, p.Gln115His and p.Leu131_Arg132insLeuCysThrGlu) were detected. The pathogenic effects of the variants detected in the OTULIN gene were determined by using Polyphen2 as "Probably Pathogenic" for the p.Val82Ile and "benign" for the p.Gln115His. At the same time, the effects of these variants on the structure and function of the OTULIN protein were investigated by in silico approaches. Both variants reduce protein stability and binding affinity.
The results of the current study suggest that the evaluation of OTULIN variants with in silico approaches will contribute to the development of personalized treatments by diagnosing the disease specific to the variant.
OTULIN 相关自身炎症综合征（ORAS）是一种常染色体隐性疾病，其特征为全身炎症、反复发作的发热。由于对导致 ORAS 的 OTULIN DNA 变异知之甚少，因此该疾病的诊断和治疗存在困难。在本研究中，我们旨在鉴定导致 ORAS 的遗传病理学的 OTULIN DNA 变异，并通过不同的生物信息学方法观察这些变异对 OTULIN 蛋白结构和功能的影响。
本研究纳入了 3230 名疑似自身炎症性疾病的个体，他们被转介到伊兹密尔大学儿童医院分子医学实验室。通过靶向下一代测序，使用包含 37 种不同自身炎症性疾病（AID）基因的面板检测 OTULIN 变异。
研究结果显示，在接受该面板检测的个体中，有 65%检测到与各种 AID 相关的 DNA 变异。在这些变异中，仅检测到三种不同的 OTULIN 变异（p.Val82Ile、p.Gln115His 和 p.Leu131_Arg132insLeuCysThrGlu）。通过 Polyphen2 将检测到的 OTULIN 基因中的变异判定为 p.Val82Ile“可能致病”，p.Gln115His“良性”，从而确定了这些变异的致病性影响。同时，通过计算机模拟方法研究了这些变异对 OTULIN 蛋白结构和功能的影响。这两种变异均降低了蛋白稳定性和结合亲和力。
本研究结果表明，通过计算机模拟方法评估 OTULIN 变异将有助于通过诊断特定于变异的疾病来制定个性化治疗方案。
