Biallelic mutations in the &lt;i&gt;SARS2&lt;/i&gt; gene presenting as congenital sideroblastic anemia

Colin, Elia; Courtois, Geneviève; Brouzes, Chantal; Pulman, Juliette; Rabant, Marion; Rötig, Agnès; Taffin, Hélène; Lion‐Lambert, Mathilde; Fabrega, Sylvie; Costa, Lydie Da; Montalembert, Mariane de; Salomon, Rémi; Hermine, Olivier; Couronné, Lucile

doi:10.3324/haematol.2021.279138

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…S6 D ). While there was no detectable difference in m 3 C status between cell lines, we note that the reduction of SARS2 to levels that affect m 3 C formation might be unfeasible since SARS2 depletion is known to reduce cell viability ( 45 ). Thus, the PHA assay might lack the sensitivity to detect subtle changes in m 3 C levels caused by incomplete depletion of SARS2.…”

Section: Resultsmentioning

confidence: 75%

“…Based upon the PHA assay, we did not detect a significant change in m 3 C formation on mt-tRNA-Ser-UGA in either SARS2knockdown cell line compared to control cells (Figure S6B). While there was no detectable difference in m 3 C status between cell lines, we note that reduction of SARS2 to levels that affect m 3 C formation might be unfeasible since SARS2 depletion is known to reduce cell viability (Colin et al 2021). Thus, the PHA assay might lack the sensitivity to detect subtle changes in m 3 C levels caused by incomplete depletion of SARS2.…”

Section: Testing the Role Of Sars2 In M 3 C Formationmentioning

confidence: 76%

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Methyltransferase METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs

Lentini

Bargabos

Chen

et al. 2022

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 75%

Section: Testing the Role Of Sars2 In M 3 C Formationmentioning

confidence: 76%

Methyltransferase METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs

Lentini

Bargabos

Chen

et al. 2022

Journal of Biological Chemistry

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“…Early-onset sideroblastic anemia has also been reported in LARS2 deficiency 80 and SARS2 deficiency 81,82 as part of a multisystem presentation. Like the other mitochondrial ARS deficiencies, most patients are transfusion-dependent and the majority die in childhood.…”

Section: Other Aminoacyl-trna Synthetase Disordersmentioning

confidence: 98%

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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Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease

Zhang

Zheng

et al. 2022

Nucleic Acids Research

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Mitochondrial translation is of high significance for cellular energy homeostasis. Aminoacyl-tRNA synthetases (aaRSs) are crucial translational components. Mitochondrial aaRS variants cause various human diseases. However, the pathogenesis of the vast majority of these diseases remains unknown. Here, we identified two novel SARS2 (encoding mitochondrial seryl-tRNA synthetase) variants that cause a multisystem disorder. c.654–14T > A mutation induced mRNA mis-splicing, generating a peptide insertion in the active site; c.1519dupC swapped a critical tRNA-binding motif in the C-terminus due to stop codon readthrough. Both mutants exhibited severely diminished tRNA binding and aminoacylation capacities. A marked reduction in mitochondrial tRNASer(AGY) was observed due to RNA degradation in patient-derived induced pluripotent stem cells (iPSCs), causing impaired translation and comprehensive mitochondrial function deficiencies. These impairments were efficiently rescued by wild-type SARS2 overexpression. Either mutation caused early embryonic fatality in mice. Heterozygous mice displayed reduced muscle tissue-specific levels of tRNASers. Our findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNASer(AGY) is a key determinant for development of SARS2-related diseases.

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Biallelic mutations in the <i>SARS2</i> gene presenting as congenital sideroblastic anemia

Abstract: Not available.

Cited by 4 publications

References 14 publications

Methyltransferase METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs

Methyltransferase METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs

Hematologic Manifestations in Primary Mitochondrial Diseases

Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease

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