The ability of chemical modifications of single nucleotides to alter the electrostatic charge, hydrophobic surface and base pairing of RNA molecules is exploited for the clinical use of stable artificial RNAs such as mRNA vaccines and synthetic small RNA molecules - to increase or decrease the expression of therapeutic proteins. Furthermore, naturally occurring biochemical modifications of nucleotides regulate RNA metabolism and function to modulate crucial cellular processes. Studies showing the mechanisms by which RNA modifications regulate basic cell functions in higher organisms have led to greater understanding of how aberrant RNA modification profiles can cause disease in humans. Together, these basic science discoveries have unravelled the molecular and cellular functions of RNA modifications, have provided new prospects for therapeutic manipulation and have led to a range of innovative clinical approaches. 

RNA modifications in physiology and disease: towards clinical applications.

Transfer (t)RNAs are 70–90 nucleotide small RNAs highly regulated by 43 different types of epitranscriptomic modifications and requiring aminoacylation (‘charging’) for mRNA decoding and protein synthesis. Smaller cleavage products of mature tRNAs, or tRNA fragments, have been linked to a broad variety of noncanonical functions, including translational inhibition and modulation of the immune response. Traditionally, knowledge about tRNA regulation in brain is derived from phenotypic exploration of monogenic neurodevelopmental and neurodegenerative diseases associated with rare mutations in tRNA modification genes. More recent studies point to the previously unrecognized potential of the tRNA regulome to affect memory, synaptic plasticity, and affective states. For example, in mature cortical neurons, cytosine methylation sensitivity of the glycine tRNA family (tRNAGly) is coupled to glycine biosynthesis and codon-specific alterations in ribosomal translation together with robust changes in cognition and depression-related behaviors. In this Review, we will discuss the emerging knowledge of the neuronal tRNA landscape, with a focus on epitranscriptomic tRNA modifications and downstream molecular pathways affected by alterations in tRNA expression, charging levels, and cleavage while mechanistically linking these pathways to neuropsychiatric disease and provide insight into future areas of study for this field. 

https://www.nature.com/articles/s41380-022-01585-9.pdf

The tRNA regulome in neurodevelopmental and neuropsychiatric disease

tRNA is one of the most conserved and abundant RNA species, which plays a key role during protein translation. tRNA molecules are post-transcriptionally modified by tRNA modifying enzymes. Since high-throughput sequencing technology has developed rapidly, tRNA modification types have been discovered in many research fields. In tRNA, numerous types of tRNA modifications and modifying enzymes have been implicated in biological functions and human diseases. In our review, we talk about the relevant biological functions of tRNA modifications, including tRNA stability, protein translation, cell cycle, oxidative stress, and immunity. We also explore how tRNA modifications contribute to the progression of human diseases. Based on previous studies, we discuss some emerging techniques for assessing tRNA modifications to aid in discovering different types of tRNA modifications.

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

https://doi.org/10.1016/j.arr.2022.101700

The epitranscriptome in ageing and stress resistance: A systematic review

Whole exome sequencing has provided significant opportunities to discover novel candidate genes for intellectual disability and autism spectrum disorders. Variants in the spectrin genes SPTAN1, SPTBN1, SPTBN2, and SPTBN4 have been associated with neurological disorders; however, SPTBN5 gene-variants have not been associated with any human disorder. This is the first report that associates SPTBN5 gene variants (ENSG00000137877: c.266A>C; p.His89Pro, c.9784G>A; p.Glu3262Lys, c.933C>G; p.Tyr311Ter, and c.8809A>T; p.Asn2937Tyr) causing neurodevelopmental phenotypes in four different families. The SPTBN5-associated clinical traits in our patients include intellectual disability (mild to severe), aggressive tendencies, accompanied by variable features such as craniofacial and physical dysmorphisms, autistic behavior, and gastroesophageal reflux. We also provide a review of the existing literature related to other spectrin genes, which highlights clinical features partially overlapping with SPTBN5.

/pdf/sptbn5-encoding-the-bv-spectrin-protein-leads-to-a-syndrome-2465dlme.pdf

SPTBN5, Encoding the βV-Spectrin Protein, Leads to a Syndrome of Intellectual Disability, Developmental Delay, and Seizures

Purpose Biallelic variants in PUS3 have recently been recognized as a rare cause of neurodevelopmental disorders. Pseudouridine synthase-3 encoded by PUS3 is an enzyme important for modification of various RNAs, including transfer RNA (tRNA). Here we present the clinical and genetic features of 21 individuals with biallelic PUS3 variants: seven new and 14 previously reported individuals, where clinical features of two were updated. Methods The clinical and genetic information were collected through collaborations or by literature search. All individuals were characterized by the local clinicians and the gene variants were identified by next generation sequencing (NGS) based methodologies. Results The clinical picture was dominated by global developmental delay, epilepsy, hypotonia and microcephaly. Gray sclera, which has previously been suggested to be a characteristic feature of PUS3-associated phenotypes, was reported in only seven individuals. The patients had some dysmorphic facial features, but a recognizable gestalt was not observed. Conclusion Homozygous and compound heterozygous PUS3 variants lead to a rare neurodevelopmental disorder. Further functional studies are necessary to understand involvement of PUS3 and tRNA biogenesis in normal and abnormal brain development.

Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders

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Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders