IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency
-
Published:2024-08-21
Issue:1
Volume:19
Page:
-
ISSN:1750-1172
-
Container-title:Orphanet Journal of Rare Diseases
-
language:en
-
Short-container-title:Orphanet J Rare Dis
Author:
Dong Qiyu, Yin Xiaojie, Fan Shuanglong, Zhong Sheng, Yang Wenxin, Chen Keer, Wang Qian, Ma Xue, Mahlatsi Refiloe Laurentinah, Yang Yanling, Lyu Jianxin, Fang Hezhi, Wang YaORCID
Abstract
Abstract
Background
Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.
Methods
Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.
Results
We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.
Conclusion
Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.
Funder
the National Natural Science Foundation of China-excellent young scientists fund the Natural Science Foundation of China Natural Science Foundation of China Zhejiang Provincial leading talents program Foundation Zhejiang Provincial Natural Science Foundation Scientific Research Fund of Zhejiang Provincial Education Department the Science and Technology Bureau of Wenzhou
Publisher
Springer Science and Business Media LLC
Reference34 articles.
1. Stenton SL, Zou Y, Cheng H, Liu Z, Wang J, Shen D, Jin H, Ding C, Tang X, Sun S. Leigh syndrome: a study of 209 patients at the Beijing children’s hospital. Ann Neurol. 2022;91(4):466–82. 2. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951;14(3):216. 3. Yahya V, Spagnolo F, Di Maggio G, Leopizzi E, De Marco P, Fortunato F, Comi GP, Rini A, Monfrini E, Di Fonzo A. Juvenile-onset dystonia with spasticity in Leigh syndrome caused by a novel NDUFA10 variant. Parkinsonism Relat Disord. 2022;104:85–7. 4. Lim AZ, Ng YS, Blain A, Jiminez-Moreno C, Alston CL, Nesbitt V, Simmons L, Santra S, Wassmer E, Blakely EL. Natural history of Leigh syndrome: a study of disease burden and progression. Ann Neurol. 2022;91(1):117–30. 5. Kistol D, Tsygankova P, Krylova T, Bychkov I, Itkis Y, Nikolaeva E, Mikhailova S, Sumina M, Pechatnikova N, Kurbatov S. Leigh syndrome: spectrum of molecular defects and clinical features in Russia. Int J Mol Sci. 2023;24(2):1597.
|
|