ArticleAmerican journal of human genetics2022
THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 43 citations in OpenAlex.
- The functions, mechanisms and clinical relevance of RNA and protein acetyltransferase NAT10: a comprehensive review.Cell biology and toxicology · 2026Review
- Cuproptosis and Mitophagy Mediated by the THUMPD1/IGF2R-Dependent Suppression of AKT and Activation of AMPK Signaling Suppress Lung Adenocarcinoma Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Structure of the NAT10 acetyltransferase and mechanism of tRNA acetylation.Nature communications · 2026Article
- RNA acetylation modification ac4C: An emerging regulatory hub of RNA metabolism disruption in Alzheimer's disease.Molecular biology reports · 2026Review
- Epitranscriptomic control of cancer: the emerging roles of m⁵C and ac⁴C RNA modifications.Cell death discovery · 2026Review
- Review
- tRNA modifications in cancer: from molecular mechanisms to clinical translation.Biomarker research · 2026Review
- NAT10 and ac4C modification in cancer immunity and metabolism: emerging mechanisms and therapeutic potential.Journal of translational medicine · 2026Review
- Metabolomic analysis of plasma and brain tissues in fentanyl-induced conditioned place preference mice.Frontiers in pharmacology · 2026Article
- RNA modifications: roles in immune cell biology and tumor regulation.Cancer cell international · 2025Review
- Neurogenetic Disorders with Hearing Loss: Mechanisms, Classifications, and Emerging Insights.Current neurology and neuroscience reports · 2025Review
- Mammalian tRNA acetylation determines translation efficiency and tRNA quality control.Nature communications · 2025Article
- Transfer RNA acetylation regulates in vivo mammalian stress signaling.Science advances · 2025Article
- Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer's disease, and late-onset Alzheimer's disease.Acta neuropathologica · 2025Article
- Exploring the impact of N4-acetylcytidine modification in RNA on non-neoplastic disease: unveiling its role in pathogenesis and therapeutic opportunities.Briefings in functional genomics · 2025Review
- Advances of NAT10 in diseases: insights from dual properties as protein and RNA acetyltransferase.Cell biology and toxicology · 2024Review
- NAT10 and cytidine acetylation in mRNA: intersecting paths in development and disease.Current opinion in genetics & development · 2024Review
- Transfer RNA acetylation regulates in vivo mammalian stress signaling.bioRxiv : the preprint server for biology · 2024Article
- Comparison of the Amyloid Plaque Proteome in Down Syndrome, Early-Onset Alzheimer's Disease and Late-Onset Alzheimer's Disease.Research square · 2024Article
- N-acetyltransferase 10 facilitates tumorigenesis of diffuse large B-cell lymphoma by regulating AMPK/mTOR signalling through N4-acetylcytidine modification of SLC30A9.Clinical and translational medicine · 2024Article
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Authors and funding
37 authors at 20 institutions in 11 countries.
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Abstract
Covalent tRNA modifications play multi-faceted roles in tRNA stability, folding, and recognition, as well as the rate and fidelity of translation, and other cellular processes such as growth, development, and stress responses. Mutations in genes that are known to regulate tRNA modifications lead to a wide array of phenotypes and diseases including numerous cognitive and neurodevelopmental disorders, highlighting the critical role of tRNA modification in human disease. One such gene, THUMPD1, is involved in regulating tRNA N4-acetylcytidine modification (ac4C), and recently was proposed as a candidate gene for autosomal-recessive intellectual disability. Here, we present 13 individuals from 8 families who harbor rare loss-of-function variants in THUMPD1. Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities. We demonstrate that the bi-allelic variants identified cause loss of function of THUMPD1 and that this defect results in a loss of ac4C modification in small RNAs, and of individually purified tRNA-Ser-CGA. We further corroborate this effect by showing a loss of tRNA acetylation in two CRISPR-Cas9-generated THUMPD1 KO cell lines. In addition, we also show the resultant amino acid substitution that occurs in a missense THUMPD1 allele identified in an individual with compound heterozygous variants results in a marked decrease in THUMPD1 stability and RNA-binding capacity. Taken together, these results suggest that the lack of tRNA acetylation due to THUMPD1 loss of function results in a syndromic form of intellectual disability associated with developmental delay, behavioral abnormalities, hearing loss, and facial dysmorphism.
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