B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene
Abstract Purpose The EARS2 gene, a member of the mt-aaRS family, encodes mitochondrial glutamyl-tRNA synthetase (GluRS), which is involved in the synthesis of mitochondrial proteins. Pathogenic defects in EARS2 may cause mitochondrial OXPHOS deficiency, which is associated with a rare autosomal-rece...
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BMC
2025-05-01
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| Series: | Italian Journal of Pediatrics |
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| Online Access: | https://doi.org/10.1186/s13052-025-01999-5 |
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| author | Yu Wen Yanmei Huang Wendi Zhang Ping Chen Xiufen Hu Xin Xiong Li Luo |
| author_facet | Yu Wen Yanmei Huang Wendi Zhang Ping Chen Xiufen Hu Xin Xiong Li Luo |
| author_sort | Yu Wen |
| collection | DOAJ |
| description | Abstract Purpose The EARS2 gene, a member of the mt-aaRS family, encodes mitochondrial glutamyl-tRNA synthetase (GluRS), which is involved in the synthesis of mitochondrial proteins. Pathogenic defects in EARS2 may cause mitochondrial OXPHOS deficiency, which is associated with a rare autosomal-recessive mitochondrial disease, leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). Methods In this study, clinical features were obtained, and whole-exome sequencing was conducted on a patient with LTBL. B- and T-cell immunophenotyping and protein expression were analyzed using flow cytometry, and B-cell metabolism was investigated using confocal microscopy. Results The patient with LTBL exhibited typical neurological manifestations, recurrent respiratory tract infections, and humoral immune disorders. Molecular analysis revealed a compound heterozygous novel mutation in c.1304T > A (p.L435Q) and a previously reported c.319 C > T (p.R107C) mutation of EARS2. The mutations led to protein structural modifications of EARS2. The patient also exhibited disrupted peripheral B-cell differentiation and B-cell receptor signal transduction. The EARS2 mutation led to decreased expression of CD38 and dysfunction of mitochondrial metabolism, with elevated reactive oxygen species levels in B cells. Conclusion We identified a novel mutation of the EARS2 gene in a patient with LTBL, expanding the mutation database. The mutation of EARS2 modified protein structure and impaired B-cell function, decreased CD38 expression, and led to dysfunction of mitochondrial metabolism, all of which may account for the recurrent respiratory tract infections and humoral immune disorders observed in LTBL. |
| format | Article |
| id | doaj-art-80686d68e79a412b85e8d5a10cdcff19 |
| institution | OA Journals |
| issn | 1824-7288 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Italian Journal of Pediatrics |
| spelling | doaj-art-80686d68e79a412b85e8d5a10cdcff192025-08-20T01:53:19ZengBMCItalian Journal of Pediatrics1824-72882025-05-0151111110.1186/s13052-025-01999-5B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 geneYu Wen0Yanmei Huang1Wendi Zhang2Ping Chen3Xiufen Hu4Xin Xiong5Li Luo6Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Purpose The EARS2 gene, a member of the mt-aaRS family, encodes mitochondrial glutamyl-tRNA synthetase (GluRS), which is involved in the synthesis of mitochondrial proteins. Pathogenic defects in EARS2 may cause mitochondrial OXPHOS deficiency, which is associated with a rare autosomal-recessive mitochondrial disease, leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). Methods In this study, clinical features were obtained, and whole-exome sequencing was conducted on a patient with LTBL. B- and T-cell immunophenotyping and protein expression were analyzed using flow cytometry, and B-cell metabolism was investigated using confocal microscopy. Results The patient with LTBL exhibited typical neurological manifestations, recurrent respiratory tract infections, and humoral immune disorders. Molecular analysis revealed a compound heterozygous novel mutation in c.1304T > A (p.L435Q) and a previously reported c.319 C > T (p.R107C) mutation of EARS2. The mutations led to protein structural modifications of EARS2. The patient also exhibited disrupted peripheral B-cell differentiation and B-cell receptor signal transduction. The EARS2 mutation led to decreased expression of CD38 and dysfunction of mitochondrial metabolism, with elevated reactive oxygen species levels in B cells. Conclusion We identified a novel mutation of the EARS2 gene in a patient with LTBL, expanding the mutation database. The mutation of EARS2 modified protein structure and impaired B-cell function, decreased CD38 expression, and led to dysfunction of mitochondrial metabolism, all of which may account for the recurrent respiratory tract infections and humoral immune disorders observed in LTBL.https://doi.org/10.1186/s13052-025-01999-5EARS2Gene mutationLTBLB cellBCR signal |
| spellingShingle | Yu Wen Yanmei Huang Wendi Zhang Ping Chen Xiufen Hu Xin Xiong Li Luo B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene Italian Journal of Pediatrics EARS2 Gene mutation LTBL B cell BCR signal |
| title | B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene |
| title_full | B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene |
| title_fullStr | B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene |
| title_full_unstemmed | B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene |
| title_short | B cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of EARS2 gene |
| title_sort | b cell dysfunction in thalamus and brainstem involvement and high lactate caused by novel mutation of ears2 gene |
| topic | EARS2 Gene mutation LTBL B cell BCR signal |
| url | https://doi.org/10.1186/s13052-025-01999-5 |
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