Nowak Albina, Haddad George, Kistler Andreas D, Nlandu-Khodo Stellor, Beuschlein Felix, Wüthrich Rudolf P, Lorenzen Johan M, Kölling Malte
Department of Endocrinology, University Hospital Zurich, Zurich, Switzerland.
Department of Internal Medicine, Psychiatric Hospital of the University of Zurich, Zurich, Switzerland.
J Med Genet. 2022 Mar;59(3):279-286. doi: 10.1136/jmedgenet-2020-107086. Epub 2021 Feb 5.
Fabry disease is a rare X-linked lysosomal storage disease caused by mutations in the galactosidase α gene. Deficient activity of α-galactosidase A leads to glycosphingolipid accumulations in multiple organs. Circular RNAs represent strong regulators of gene expression. Their circular structure ensures high stability in blood. We hypothesised that blood-based circular RNA profiles improve phenotypic assignment and therapeutic monitoring of Fabry disease.
A genome-wide circular RNA expression analysis was performed in blood of genetically diagnosed patients with Fabry disease (n=58), age-matched and sex-matched healthy volunteers (n=14) and disease control patients with acute kidney injury (n=109). Most highly dysregulated circular RNAs were validated by quantitative real-time PCR. Circular RNA biomarker sensitivity, specificity, predictive values and area under the curve (AUC) were determined. Linear regression analyses were conducted for validated circular RNA biomarkers and clinical patient characteristics.
A distinct circular RNA transcriptome signature identified patients with Fabry disease. Level of circular RNAs (AUC=0.73), (AUC=0.8) and (AUC=0.8) distinguished patients with Fabry disease from both healthy controls and patients with acute kidney injury. was, furthermore, female-specifically expressed. Circular RNA level were significantly related to galactosidase α gene mutations, early symptoms, phenotypes, disease severities, specific therapies and long-term complications of Fabry disease.
The discovery of circular RNA-based and Fabry disease-specific biomarkers may advance future diagnosis of Fabry disease and help to distinguish related phenotypes.
法布里病是一种罕见的X连锁溶酶体贮积病，由α-半乳糖苷酶基因的突变引起。α-半乳糖苷酶A活性不足导致糖鞘脂在多个器官中蓄积。环状RNA是基因表达的强有力调节因子。它们的环状结构确保了在血液中的高稳定性。我们假设基于血液的环状RNA谱可改善法布里病的表型判定和治疗监测。
对经基因诊断的法布里病患者（n = 58）、年龄和性别匹配的健康志愿者（n = 14）以及急性肾损伤疾病对照患者（n = 109）的血液进行全基因组环状RNA表达分析。通过定量实时PCR验证了大多数高度失调的环状RNA。测定了环状RNA生物标志物的敏感性、特异性、预测值和曲线下面积（AUC）。对经验证的环状RNA生物标志物和临床患者特征进行了线性回归分析。
独特的环状RNA转录组特征可识别法布里病患者。环状RNA （AUC = 0.73）、 （AUC = 0.8）和 （AUC = 0.8）的水平可将法布里病患者与健康对照者和急性肾损伤患者区分开来。此外， 是女性特异性表达的。环状RNA水平与法布里病的α-半乳糖苷酶基因突变、早期症状、表型、疾病严重程度、特定治疗和长期并发症显著相关。
基于环状RNA的法布里病特异性生物标志物的发现可能会推动法布里病未来的诊断，并有助于区分相关表型。
