Sideroblastic anemia with myopathy secondary to novel, pathogenic missense variants in the <i>YARS2</i> gene

Smith, Frances; Hopton, Sila; Dallabona, Cristina; Gilberti, Micol; Falkous, Gavin; Norwood, Fiona; Donnini, Claudia; Gorman, Gráinne; Clark, Barnaby; Taylor, Robert W.; Kulasekararaj, Austin

doi:10.3324/haematol.2018.194464

Cited by 7 publications

(4 citation statements)

References 16 publications

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“… 24 According to Pubmed and the Human Genome Mutation Database, pathogenic YARS2 mutations have been linked to myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2), 27 Cardiomyopathy, 28 and Sideroblastic anemia with myopathy. 29 In these studies, the patients all carried pathogenic mutations which leads to abnormal mitochondrial function in various tissues, especially skeletal muscles, neurons, etc., indicating that stable expression of YARS2 is essential for cell function and tissue development.…”

Section: Discussionmentioning

confidence: 99%

Targeting mitochondrial tyrosyl-tRNA synthetase YARS2 suppresses colorectal cancer progression

Fang

Lin

Gao

et al. 2022

Cancer Biology & Therapy

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Defects in tRNA expressions and modifications had been linked to various types of tumorigenesis and progression in recent studies, including colorectal cancer. In the present study, we evaluated transcript levels of mitochondrial tyrosyl-tRNA synthetase YARS2 in both colorectal cancer tissues and normal colorectal tissues using qRT-PCR. The results revealed that the mRNA expression level of YARS2 in colorectal cancer tissues was significantly higher than those in normal intestinal tissues. Knockdown of YARS2 in human colon cancer cell-line SW620 leads to significant inhibition of cell proliferation and migration. The steady-state level of tRNATyr, OCR, and ATP synthesis were decreased in the YARS2 knockdown cells. Moreover, our data indicated that inhibition of YARS2 is associated with increased reactive oxygen species levels which sensitize these cells to 5-FU treatment. In conclusion, our study revealed that targeting YARS2 could inhibit colorectal cancer progression. Thus, YARS2 might be a carcinogenesis candidate gene and can serve as a potential target for clinical therapy.

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Section: Discussionmentioning

confidence: 99%

Targeting mitochondrial tyrosyl-tRNA synthetase YARS2 suppresses colorectal cancer progression

Fang

Lin

Gao

et al. 2022

Cancer Biology & Therapy

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“…Similar to Pearson syndrome (and unlike many of the other sideroblastic anemias), the circulating peripheral blood cells are normocytic or macrocytic in YARS2 deficiency. 78 Management of YARS2 deficiency is primarily organspecific. Those with severe anemia are often transfusion-dependent by mid-childhood, and hearing and vision are often not affected, which are key distinguishing features compared with Pearson syndrome.…”

Section: Barth Syndromementioning

confidence: 99%

“…2) and a reversed myeloid-erythroid ratio. Similar to Pearson syndrome (and unlike many of the other sideroblastic anemias), the circulating peripheral blood cells are normocytic or macrocytic in YARS2 deficiency 78 …”

Section: Yars2 Deficiencymentioning

confidence: 99%

Hematologic Manifestations in Primary Mitochondrial Diseases

Selvanathan,

Teo,

Parayil Sankaran

2024

Journal of Pediatric Hematology/Oncology

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Primary mitochondrial disorders (PMDs) are known for their pleiotropic manifestations in humans, affecting almost any organ or system at any time. Hematologic manifestations, such as cytopenias and sideroblastic anemia, occur in 10% to 30% of patients with confirmed PMDs. These can be the initial presenting features or complications that develop over time. Surveillance for these manifestations allows for prompt identification and treatment. This article provides an overview of the pathophysiology underpinning the hematologic effects of mitochondrial dysfunction, discussing the 3 key roles of the mitochondria in hematopoiesis: providing energy for cell differentiation and function, synthesizing heme, and generating iron-sulfur clusters. Subsequently, the diagnosis and management of mitochondrial disorders are discussed, focusing on hematologic manifestations and the specific conditions commonly associated with them. Through this, we aimed to provide a concise point of reference for those considering a mitochondrial cause for a patient’s hematologic abnormality, or for those considering a hematologic manifestation in a patient with known or suspected mitochondrial disease.

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“…As a yeast model paradigm for this class of genes, we report the study of mutations in YARS2 , encoding for the mitochondrial tyrosyl-tRNA synthetase. Mutations in this gene are associated with phenotypic heterogeneity ranging from infantile-onset and often fatal myopathy, lactic acidosis and sideroblastic anemia type 2 (MLASA2) syndrome to later adolescent-onset, slowly progressive myopathy or congenital sideroblastic anemia [ 22 , 23 , 24 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Functional Studies Of Mt Ars Genes Mutations In Yeastmentioning

confidence: 99%

Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants

Figuccia

Degiorgi

Berti

et al. 2021

IJMS

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In most eukaryotes, mitochondrial protein synthesis is essential for oxidative phosphorylation (OXPHOS) as some subunits of the respiratory chain complexes are encoded by the mitochondrial DNA (mtDNA). Mutations affecting the mitochondrial translation apparatus have been identified as a major cause of mitochondrial diseases. These mutations include either heteroplasmic mtDNA mutations in genes encoding for the mitochondrial rRNA (mtrRNA) and tRNAs (mttRNAs) or mutations in nuclear genes encoding ribosomal proteins, initiation, elongation and termination factors, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases (mtARSs). Aminoacyl-tRNA synthetases (ARSs) catalyze the attachment of specific amino acids to their cognate tRNAs. Differently from most mttRNAs, which are encoded by mitochondrial genome, mtARSs are encoded by nuclear genes and then imported into the mitochondria after translation in the cytosol. Due to the extensive use of next-generation sequencing (NGS), an increasing number of mtARSs variants associated with large clinical heterogeneity have been identified in recent years. Being most of these variants private or sporadic, it is crucial to assess their causative role in the disease by functional analysis in model systems. This review will focus on the contributions of the yeast Saccharomyces cerevisiae in the functional validation of mutations found in mtARSs genes associated with human disorders.

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Sideroblastic anemia with myopathy secondary to novel, pathogenic missense variants in the YARS2 gene

Cited by 7 publications

References 16 publications

Targeting mitochondrial tyrosyl-tRNA synthetase YARS2 suppresses colorectal cancer progression

Targeting mitochondrial tyrosyl-tRNA synthetase YARS2 suppresses colorectal cancer progression

Hematologic Manifestations in Primary Mitochondrial Diseases

Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants

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