Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder DOI Creative Commons
Stéphanie Efthymiou,

Cailyn P Leo,

Chenghong Deng

et al.

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants tRNA-modification enzymes have been implicated wide range human neurodevelopmental neurological disorders. However, the molecular basis for many these disorders remains unknown. Here, we describe comprehensive cohort 43 individuals from 31 unrelated families with bi-allelic methyltransferase 1 (TRMT1). These present disorder universally characterized by developmental delay intellectual disability, accompanied variable behavioral abnormalities, epilepsy, facial dysmorphism. identified include ultra-rare TRMT1 variants, comprising missense predicted loss-of-function which segregate observed clinical pathology. Our findings reveal that several lead to mis-splicing consequent loss protein accumulation. Moreover, cells derived harboring exhibit deficiency modifications catalyzed TRMT1. Molecular analysis reveals distinct regions required activity binding. Notably, depletion Trmt1 zebrafish is sufficient induce phenotypes along gene-expression changes associated disrupted cell cycle, immune response, neurodegenerative Altogether, demonstrate TRMT1-catalyzed leads disability provides insight into underpinnings caused pathogenic variants.

Language: Английский

TRMT1L-catalyzed m22G27 on tyrosine tRNA is required for efficient mRNA translation and cell survival under oxidative stress DOI Creative Commons
Sseu-Pei Hwang, Han Liao,

Katherine Barondeau

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(1), P. 115167 - 115167

Published: Jan. 1, 2025

Highlights•TRMT1L is the elusive RNA methyltransferase catalyzing m22G at position 27 on tyrosine tRNA•TRMT1L also required to maintain acp3U and D modifications a subset of tRNAs•TRMT1L depletion destabilizes tRNA reduces global translation efficiency•Depletion TRMT1L cell survival under oxidative stress conditionsSummarytRNA are critical for several aspects their functions, including decoding, folding, stability. Using multifaceted approach encompassing eCLIP-seq nanopore tRNA-seq, we show that human interacts with component Rix1 ribosome biogenesis complex binds 28S rRNA as well tRNAs. Mechanistically, demonstrate responsible N2,N2-dimethylguanosine (m22G) solely tRNA-Tyr-GUA. Surprisingly, impaired deposition 3-(3-amino-3-carboxypropyl) uridine (acp3U) dihydrouridine tRNA-Tyr-GUA, Cys-GCA, Ala-CGC. knockout cells have marked decrease in tRNA-Tyr-GUA levels, coinciding reduction rates hypersensitivity stress. Our results establish m22G27 modification Tyr, resolving long-standing gap knowledge highlighting its potential role circuit crucial regulation response.Graphical abstract

Language: Английский

Citations

3
Neurological Diseases Caused by Loss of Transfer RNA Modifications: Commonalities in Their Molecular Pathogenesis DOI
Takeshi Chujo, Kazuhito Tomizawa

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169047 - 169047

Published: March 1, 2025

Language: Английский

Citations

0
Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder DOI Creative Commons
Stéphanie Efthymiou,

Cailyn P Leo,

Chenghong Deng

et al.

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants tRNA-modification enzymes have been implicated wide range human neurodevelopmental neurological disorders. However, the molecular basis for many these disorders remains unknown. Here, we describe comprehensive cohort 43 individuals from 31 unrelated families with bi-allelic methyltransferase 1 (TRMT1). These present disorder universally characterized by developmental delay intellectual disability, accompanied variable behavioral abnormalities, epilepsy, facial dysmorphism. identified include ultra-rare TRMT1 variants, comprising missense predicted loss-of-function which segregate observed clinical pathology. Our findings reveal that several lead to mis-splicing consequent loss protein accumulation. Moreover, cells derived harboring exhibit deficiency modifications catalyzed TRMT1. Molecular analysis reveals distinct regions required activity binding. Notably, depletion Trmt1 zebrafish is sufficient induce phenotypes along gene-expression changes associated disrupted cell cycle, immune response, neurodegenerative Altogether, demonstrate TRMT1-catalyzed leads disability provides insight into underpinnings caused pathogenic variants.

Language: Английский

Citations

0