Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation: A Novel <scp><i>DARS2</i></scp> Mutation and Intra‐Familial Heterogeneity

Li, Jeng Lin; Lee, Ni‐Chung; Chen, Pin Shiuan; Lee, Gin Hoong; Wu, Ruey‐Meei

doi:10.1002/mdc3.13281

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…Relatedly, it is possible that certain variants might affect only canonical aminoacylation activity and not non-canonical functions, and vice versa, which could contribute to variant-specific phenotypes. There are multiple mt-ARSs that contain protein domains that are potentially unrelated to canonical functions (e.g., DARS2 has a bacterial extension [ 111 ], and SARS2 and VARS2 contain C-terminal sequences that are uncharacterized [ 21 ]), and these domains are good candidates for identifying non-canonical functions. Thus far, the majority of mt-ARS variants tested have demonstrated loss-of-function effects; pathogenic variants that preserve aminoacylation function may also point toward effects on non-canonical functions.…”

Section: What Additional Functions Do Mt-arss Have In the Mitochondria?mentioning

confidence: 99%

The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease

Greco

Antonellis

2022

Genes

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Aminoacyl-tRNA synthetases (ARSs) are highly conserved essential enzymes that charge tRNA with cognate amino acids—the first step of protein synthesis. Of the 37 nuclear-encoded human ARS genes, 17 encode enzymes are exclusively targeted to the mitochondria (mt-ARSs). Mutations in nuclear mt-ARS genes are associated with rare, recessive human diseases with a broad range of clinical phenotypes. While the hypothesized disease mechanism is a loss-of-function effect, there is significant clinical heterogeneity among patients that have mutations in different mt-ARS genes and also among patients that have mutations in the same mt-ARS gene. This observation suggests that additional factors are involved in disease etiology. In this review, we present our current understanding of diseases caused by mutations in the genes encoding mt-ARSs and propose explanations for the observed clinical heterogeneity.

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Section: What Additional Functions Do Mt-arss Have In the Mitochondria?mentioning

confidence: 99%

The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease

Greco

Antonellis

2022

Genes

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“…This mitochondrial enzyme plays a crucial role in the aminoacylation of aspartyl-tRNA explicitly. Oftentimes, mutations in DARS2 result in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation [ 4 , 5 ]. Previous reports highlighted the critical role of DARS2 in cancer progression.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA (let-7b-5p)-targeted DARS2 regulates lung adenocarcinoma growth by PI3K/AKT signaling pathway

XU,

CHEN

2024

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Background The aberrant intracellular expression of a mitochondrial aspartyl-tRNA synthetase 2 (DARS2) has been reported in human cancers. Nevertheless, its critical role and detailed mechanism in lung adenocarcinoma (LUAD) remain unexplored. Methods Initially, The Cancer Genome Atlas (TCGA)-based Gene Expression Profiling Interactive Analysis (GEPIA) database ( http://gepia.cancer-pku.cn/ ) was used to analyze the prognostic relevance of DARS2 expression in LUAD. Further, cell counting kit (CCK)-8, immunostaining, and transwell invasion assays in LUAD cell lines in vitro , as well as DARS2 silence on LUAD by tumorigenicity experiments in vivo in nude mice, were performed. Besides, we analyzed the expression levels of p-PI3K (phosphorylated-Phosphotylinosital3 kinase), PI3K, AKT (Protein Kinase B), p-AKT (phosphorylated-Protein Kinase B), PCNA (proliferating cell nuclear antigen), cleaved-caspase 3, E-cadherin, and N-cadherin proteins using the Western blot analysis. Results LUAD tissues showed higher DARS2 expression compared to normal tissues. Upregulation of DARS2 could be related to Tumor-Node-Metastasis (TNM) stage, high lymph node metastasis, and inferior prognosis. DARS2 silence decreased the proliferation, migration, and invasion abilities of LUAD cells. In addition, the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved-caspase 3 and E-cadherin expressions in LUAD cells, coupled with the inactivation of the PI3K/AKT signaling pathway. Moreover, DARS2 silence impaired the tumorigenicity of LUAD in vivo . Interestingly, let-7b-5p could recognize DARS2 through a complementary sequence. Mechanistically, the increased let-7b-5p expression attenuated the promo-oncogenic action of DARS2 during LUAD progression, which were inversely correlated to each other in the LUAD tissues. Conclusion In summary, let-7b-5p downregulated DARS2 expression, regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.

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Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

Wongkittichote

Magistrati²,

Shimony³

et al. 2022

Molecular Genetics and Metabolism

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Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation: A Novel DARS2 Mutation and Intra‐Familial Heterogeneity

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 3 publications

References 17 publications

The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease

The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease

MicroRNA (let-7b-5p)-targeted DARS2 regulates lung adenocarcinoma growth by PI3K/AKT signaling pathway

Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation

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