Mendes Marisa I, Wolf Nicole I, Rudinger-Thirion Joëlle, Lenz Dominic, Frugier Magali, Verloo Patrick, Mandel Hanna, Manor Joshua, Kassel Rachel, Corpeleijn Willemijn E, van der Rijt Sanne, Schroor Elsbeth M, van Dooren Silvy J M, Staufner Christian, Salomons Gajja S, Smith Desirée E C
Department Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
Nucleic Acids Res. 2024 Dec 11;52(22):e107. doi: 10.1093/nar/gkae1134.
In recent years, pathogenic variants in ARS genes, encoding aminoacyl-tRNA synthetases (aaRSs), have been associated with human disease. Patients harbouring pathogenic variants in ARS genes have clinical signs partly unique to certain aaRSs defects, partly overlapping between the different aaRSs defects. Diagnosis relies mostly on genetics and remains challenging, often requiring functional validation of new ARS variants. In this study, we present the development and validation of a method to simultaneously determine aminoacylation activities of all cytosolic aaRSs (encoded by ARS1 genes) in one single cell lysate, improving diagnosis in suspected ARS1 disorders and facilitating functional characterization of ARS1 variants of unknown significance. As proof of concept, we show enzyme activities of five individuals with variants in different ARS1 genes, demonstrating the usability and convenience of the presented method.
近年来，编码氨酰 - tRNA合成酶（aaRSs）的ARS基因中的致病变体已与人类疾病相关联。携带ARS基因致病变体的患者具有部分特定于某些aaRSs缺陷的临床体征，部分在不同aaRSs缺陷之间重叠。诊断主要依赖遗传学，仍然具有挑战性，通常需要对新的ARS变体进行功能验证。在本研究中，我们展示了一种方法的开发和验证，该方法可在单个细胞裂解物中同时测定所有胞质aaRSs（由ARS1基因编码）的氨酰化活性，改善疑似ARS1疾病的诊断，并促进对意义不明的ARS1变体的功能表征。作为概念验证，我们展示了五名具有不同ARS1基因变体的个体的酶活性，证明了所提出方法的可用性和便利性。
