🎙️Episode 6: Cracking the Code: How TRMT1 Mutations Disrupt tRNA and Drive Neurodevelopmental Disorders

🎙️ 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

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