Show Notes
️ Episode 6: Cracking the Code: How TRMT1 Mutations Disrupt tRNA and Drive Neurodevelopmental Disorders
In this episode of Base by Base, we dive into a 2025 study published in The American Journal of Human Genetics that sheds light on how pathogenic variants in the TRMT1 gene disrupt tRNA modification, leading to a newly characterized neurodevelopmental disorder.
Led by Efthymiou and colleagues, the study describes 43 individuals from 31 families carrying biallelic TRMT1 variants. Through human cell models, patient-derived cells, and zebrafish experiments, the authors uncover how defective TRMT1-mediated tRNA methylation can impair brain development and function.
Key insights include:
Discovery of 24 ultra-rare TRMT1 variants (missense, frameshift, and splicing) all clustered in functional domains critical for tRNA modification.
Aberrant splicing and loss of TRMT1 protein were observed in several variants, confirmed via minigene assays and immunoblotting.
Deficient tRNA modifications in patient-derived cells link directly to impaired global protein synthesis.
Zebrafish models with trmt1 knockout recapitulate key features such as developmental delay, behavioral abnormalities, and brain structural defects.
Transcriptomic analyses revealed dysregulation of genes involved in cell cycle control, immune response, and neurodegeneration pathways.
This episode highlights how disruption of a fundamental RNA modification pathway—previously underappreciated—can drive human cognitive disorders, opening new avenues for diagnosis and potentially for future therapeutic strategies.
Reference:
Efthymiou, S., Leo, C.P., Deng, C., et al. (2025). Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder. The American Journal of Human Genetics, 112(5), 1–22. https://doi.org/10.1016/j.ajhg.2025.03.015
License: This content is distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). For more information, visit https://creativecommons.org/licenses/by/4.0/
