Aminoacylation‐defective bi‐allelic mutations in human <scp>EPRS1</scp> associated with psychomotor developmental delay, epilepsy, and deafness

Jin, Danni; Wek, Sheree A.; Cordova, Ricardo A.; Wek, Ronald C.; Lacombe, Didier; Michaud, Vincent; Musier‐Forsyth, Karin

doi:10.1111/cge.14269

Cited by 6 publications

(6 citation statements)

References 16 publications

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“…However, low levels of EPRS1 might specifically inhibit protein synthesis in critical cells particularly sensitive to tRNA charging activity, e.g., in myelinating oligodendrocytes. Consistent with tissue‐selective responses to aminoacylation defects, fibroblasts from patients with compound heterozygous mutations in the GluRS region of EPRS1 exhibited normal growth rates despite severely compromised tRNA charging activity of recombinant protein in vitro 80 . Although genetic defects in two other cytosolic aaRSs, namely, DARS1 and RARS1, also cause HLD 10 , 81 , 82 , defects in at least ten cytosolic aaRSs cause distinct neurologic disorders including encephalopathy, microcephaly, as well as peripheral neuropathy 1 , 11 , suggesting that aaRS inhibition of protein synthesis is unlikely to be the principal etiology underlying HLD.…”

Section: Discussionmentioning

confidence: 66%

Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility

Khan,

Ramachandiran,

Vasu

et al. 2024

Nat Commun

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Hypomyelinating leukodystrophy (HLD) is an autosomal recessive disorder characterized by defective central nervous system myelination. Exome sequencing of two siblings with severe cognitive and motor impairment and progressive hypomyelination characteristic of HLD revealed homozygosity for a missense single-nucleotide variant (SNV) in EPRS1 (c.4444 C > A; p.Pro1482Thr), encoding glutamyl-prolyl-tRNA synthetase, consistent with HLD15. Patient lymphoblastoid cell lines express markedly reduced EPRS1 protein due to dual defects in nuclear export and cytoplasmic translation of variant EPRS1 mRNA. Variant mRNA exhibits reduced METTL3 methyltransferase-mediated writing of N6-methyladenosine (m6A) and reduced reading by YTHDC1 and YTHDF1/3 required for efficient mRNA nuclear export and translation, respectively. In contrast to current models, the variant does not alter the sequence of m6A target sites, but instead reduces their accessibility for modification. The defect was rescued by antisense morpholinos predicted to expose m6A sites on target EPRS1 mRNA, or by m6A modification of the mRNA by METTL3-dCas13b, a targeted RNA methylation editor. Our bioinformatic analysis predicts widespread occurrence of SNVs associated with human health and disease that similarly alter accessibility of distal mRNA m6A sites. These results reveal a new RNA-dependent etiologic mechanism by which SNVs can influence gene expression and disease, consequently generating opportunities for personalized, RNA-based therapeutics targeting these disorders.

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Section: Discussionmentioning

confidence: 66%

Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility

Khan,

Ramachandiran,

Vasu

et al. 2024

Nat Commun

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“…Immunoblotting, enzymatic activity assays, and mass spectrometric analysis revealed that EPRS-related leukodystrophy was related to abnormal protein production with or without abnormal aminoacylation but was unlikely to be related to MSC assembly 94 . Another report identified heterozygous variants in EPRS1 in a 4year-old patient presenting with psychomotor retardation, seizures, and deafness 95 . The mutated residues were identified in the EARS1 domain, which is conserved among species 95 .…”

Section: Other Disease-related Functionsmentioning

confidence: 97%

“…Another report identified heterozygous variants in EPRS1 in a 4year-old patient presenting with psychomotor retardation, seizures, and deafness 95 . The mutated residues were identified in the EARS1 domain, which is conserved among species 95 . These studies reflect potential connections between EPRS1 and neurological diseases that are caused mainly by abnormalities in canonical tRNA aminoacylation.…”

Section: Other Disease-related Functionsmentioning

confidence: 97%

Phosphocode-dependent glutamyl-prolyl-tRNA synthetase 1 signaling in immunity, metabolism, and disease

Lee,

Hwang,

Kim

2023

Exp Mol Med

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Ubiquitously expressed aminoacyl-tRNA synthetases play essential roles in decoding genetic information required for protein synthesis in every living species. Growing evidence suggests that they also function as crossover mediators of multiple biological processes required for homeostasis. In humans, eight cytoplasmic tRNA synthetases form a central machinery called the multi-tRNA synthetase complex (MSC). The formation of MSCs appears to be essential for life, although the role of MSCs remains unclear. Glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is the most evolutionarily derived component within the MSC that plays a critical role in immunity and metabolism (beyond its catalytic role in translation) via stimulus-dependent phosphorylation events. This review focuses on the role of EPRS1 signaling in inflammation resolution and metabolic modulation. The involvement of EPRS1 in diseases such as cancer is also discussed.

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“…Hearing loss is a common feature of recessive diseases caused by mutations in several ARSs, including EPRS1 , HARS1 , HARS2, IARS2, KARS1, LARS2 and NARS2 ( Pierce et al, 2011 ; Puffenberger et al, 2012 ; Pierce et al, 2013 ; Santos-Cortez et al, 2013 ; Simon et al, 2015 ; Soldà et al, 2016 ; Sun et al, 2019 ; Jin et al, 2022 ). A recent study investigated the consequences of selective Hars2 knockout ( Hars2- cKO) in the inner hair cells (IHC) and outer hair cells (OHC) of the cochlea in mice using the Cre-loxP system, with Cre recombinase expression driven by the promoter for the hair cell-selective transcription factor Gfi1 ( Xu et al, 2021 ).…”

Section: Animal Model Systems For Studying Recessive Ars Diseasesmentioning

confidence: 99%

Recessive aminoacyl-tRNA synthetase disorders: lessons learned from in vivo disease models

et al. 2023

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Protein synthesis is a fundamental process that underpins almost every aspect of cellular functioning. Intriguingly, despite their common function, recessive mutations in aminoacyl-tRNA synthetases (ARSs), the family of enzymes that pair tRNA molecules with amino acids prior to translation on the ribosome, cause a diverse range of multi-system disorders that affect specific groups of tissues. Neurological development is impaired in most ARS-associated disorders. In addition to central nervous system defects, diseases caused by recessive mutations in cytosolic ARSs commonly affect the liver and lungs. Patients with biallelic mutations in mitochondrial ARSs often present with encephalopathies, with variable involvement of peripheral systems. Many of these disorders cause severe disability, and as understanding of their pathogenesis is currently limited, there are no effective treatments available. To address this, accurate in vivo models for most of the recessive ARS diseases are urgently needed. Here, we discuss approaches that have been taken to model recessive ARS diseases in vivo, highlighting some of the challenges that have arisen in this process, as well as key results obtained from these models. Further development and refinement of animal models is essential to facilitate a better understanding of the pathophysiology underlying recessive ARS diseases, and ultimately to enable development and testing of effective therapies.

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Aminoacylation‐defective bi‐allelic mutations in human EPRS1 associated with psychomotor developmental delay, epilepsy, and deafness

Cited by 6 publications

References 16 publications

Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility

Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility

Phosphocode-dependent glutamyl-prolyl-tRNA synthetase 1 signaling in immunity, metabolism, and disease

Recessive aminoacyl-tRNA synthetase disorders: lessons learned from in vivo disease models

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