Show Notes
Efthymiou S et al., The American Journal of Human Genetics - A global cohort study identifies bi-allelic TRMT1 variants that cause developmental delay and intellectual disability, links those variants to reduced tRNA m2,2G modification in patient cells, and models TRMT1 deficiency in zebrafish to reveal developmental and transcriptomic consequences. Key terms: TRMT1, tRNA modification, intellectual disability, m2,2G, zebrafish.
Study Highlights:
The authors report 43 affected individuals from 31 families with bi-allelic TRMT1 variants (missense, splice, frameshift) presenting with universal developmental delay and intellectual disability and variable seizures and dysmorphism. Functional assays show many variants cause aberrant splicing or reduced TRMT1 protein, and patient-derived cells exhibit markedly reduced m2,2G tRNA modifications by primer extension and LC-MS. Variant-specific effects map to distinct regions of TRMT1 that differentially impair tRNA binding or catalytic activity, and TRMT1 variants show variable rescue in TRMT1-KO cells. CRISPR trmt1-deficient zebrafish display developmental delay, reduced brain size, decreased neuronal proliferation, behavioral changes, and transcriptomic shifts implicating cell-cycle and immune pathways.
Conclusion:
Loss of TRMT1-catalyzed m2,2G tRNA modification underlies an autosomal-recessive neurodevelopmental disorder; TRMT1 should be considered in diagnostic testing for unexplained intellectual disability and as a model for tRNA-modification–linked neuropathology.
QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-04-17.
Scope: article metadata and core scientific claims from the narration, excluding analogies, intro/outro, and music.
Factual QC score: 10/10.
Metadata QC score: 10/10.
Supported core claims: 7.
Claims flagged for review: 0.
Metadata checks passed: 4.
Metadata issues found: 0.
QC result: Pass.
Music:
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Article title:
Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
First author:
Efthymiou S
Journal:
The American Journal of Human Genetics
DOI:
10.1016/j.ajhg.2025.03.015
Reference:
Efthymiou S, Leo CP, Deng C, et al. Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder. Am J Hum Genet. 2025;112:1117–1138. doi:10.1016/j.ajhg.2025.03.015
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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Episode link: https://basebybase.com/episodes/cracking-the-code-how-trmt1-mutations-disrupt-trna-and-drive-neurodevelopmental-disorders
