ArticleHuman mutation2022
Destabilization of mutated human PUS3 protein causes intellectual disability.
Article in Human mutation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 23 citations in OpenAlex.
- The NeuroWES project: lessons learned from comprehensive phenotyping and genetic analysis of neurodevelopmental disorders over a decade.Human genetics · 2026Article
- The impact of psuedouridine modification on human tRNA.Biochemical Society transactions · 2026Review
- Role of mitochondrial translation in modulating inflammatory disease outcome: Current knowledge and future perspectives.The Journal of biological chemistry · 2026Review
- Neuromodulatory role and therapeutic potential of N 6 -methyladenosine RNA methylation in neurodegenerative diseases.Neural regeneration research · 2026Article
- Expandingthe Phenotypic Spectrum ofMolecular syndromology · 2026Article
- Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.Molecular neurobiology · 2025Review
- A comprehensive tRNA pseudouridine map uncovers targets dependent on human stand-alone pseudouridine synthases.Nature cell biology · 2025Article
- Advances in RNA modification in myocardial fibrosis (Review).International journal of molecular medicine · 2025Review
- Mechanistic insight into the pseudouridylation of RNA.RNA biology · 2025Review
- Determining the effects of pseudouridine incorporation on human tRNAs.The EMBO journal · 2025Article
- RNA modifications and their role in gene expression.Frontiers in molecular biosciences · 2025Review
- Molecular basis for thiocarboxylation and release of Urm1 by its E1-activating enzyme Uba4.Nucleic acids research · 2024Article
- RNA modifications: emerging players in the regulation of reproduction and development.Acta biochimica et biophysica Sinica · 2024Review
- The molecular basis of tRNA selectivity by human pseudouridine synthase 3.Molecular cell · 2024Article
- Pseudouridine andRSC chemical biology · 2024Review
- Why U matters: detection and functions of pseudouridine modifications in mRNAs.Trends in biochemical sciences · 2024Review
- RNA modification in cardiovascular disease: implications for therapeutic interventions.Signal transduction and targeted therapy · 2023Review
- Epitranscriptomics as a New Layer of Regulation of Gene Expression in Skeletal Muscle: Known Functions and Future Perspectives.International journal of molecular sciences · 2023Review
- Identification and validation of key biomarkers based on RNA methylation genes in sepsis.Frontiers in immunology · 2023Article
- Destabilization of mutated human PUS3 protein causes intellectual disability.Human mutation · 2022Article
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pseudouridine (Ψ) is an RNA base modification ubiquitously found in many types of RNAs. In humans, the isomerization of uridine is catalyzed by different stand-alone pseudouridine synthases (PUS). Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been identified in patients with neurodevelopmental disorders. However, the underlying molecular mechanisms that cause the disease phenotypes remain elusive. Here, we utilize exome sequencing to identify genomic variants that lead to a homozygous amino acid substitution (p.[(Tyr71Cys)];[(Tyr71Cys)]) in human PUS3 of two affected individuals and a compound heterozygous substitution (p.[(Tyr71Cys)];[(Ile299Thr)]) in a third patient. We obtain wild-type and mutated full-length human recombinant PUS3 proteins and characterize the enzymatic activity in vitro. Unexpectedly, we find that the p.Tyr71Cys substitution neither affect tRNA binding nor pseudouridylation activity in vitro, but strongly impair the thermostability profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation. Concomitantly, we observe that the PUS3 protein levels as well as the level of PUS3-dependent Ψ levels are strongly reduced in fibroblasts derived from all three patients. In summary, our results directly illustrate the link between the identified PUS3 variants and reduced Ψ levels in the patient cells, providing a molecular explanation for the observed clinical phenotypes.
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