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

Debjit Khan, Iyappan Ramachandiran, Kommireddy Vasu, Arnab China, Krishnendu Khan, Fabio Cumbo, Dalia Halawani, Fulvia Terenzi, Isaac Zin, Briana Long, Gregory Costain, Susan Blaser, Amanda Carnevale, Valentin Gogonea, Ranjan Dutta, Daniel Blankenberg, Grace Yoon () and Paul L. Fox ()
Additional contact information
Debjit Khan: Cleveland Clinic, Lerner Research Institute
Iyappan Ramachandiran: Cleveland Clinic, Lerner Research Institute
Kommireddy Vasu: Cleveland Clinic, Lerner Research Institute
Arnab China: Cleveland Clinic, Lerner Research Institute
Krishnendu Khan: Cleveland Clinic, Lerner Research Institute
Fabio Cumbo: Cleveland Clinic, Lerner Research Institute
Dalia Halawani: Cleveland Clinic, Lerner Research Institute
Fulvia Terenzi: Cleveland Clinic, Lerner Research Institute
Isaac Zin: Cleveland Clinic, Lerner Research Institute
Briana Long: Cleveland Clinic, Lerner Research Institute
Gregory Costain: The Hospital for Sick Children, University of Toronto
Susan Blaser: The Hospital for Sick Children, University of Toronto
Amanda Carnevale: The Hospital for Sick Children, University of Toronto
Valentin Gogonea: Cleveland State University
Ranjan Dutta: Cleveland Clinic, Lerner Research Institute
Daniel Blankenberg: Cleveland Clinic, Lerner Research Institute
Grace Yoon: The Hospital for Sick Children, University of Toronto
Paul L. Fox: Cleveland Clinic, Lerner Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48549-x

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