The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance

Abstract

FTSJ1 is a conserved human 2′-O-methyltransferase (Nm-MTase) that modifies several tRNAs at position 32 and the wobble position 34 in the anticodon loop. Its loss of function has been linked to X-linked intellectual disability (XLID), and more recently to cancers. However, the molecular mechanisms underlying these pathologies are currently unclear. Here, we report a novelFTSJ1pathogenic variant from an X-linked intellectual disability patient. Using blood cells derived from this patient and other affected individuals carryingFTSJ1mutations, we performed an unbiased and comprehensive RiboMethSeq analysis to map the ribose methylation on all human tRNAs and identify novel targets. In addition, we performed a transcriptome analysis in these cells and found that several genes previously associated with intellectual disability and cancers were deregulated. We also found changes in the miRNA population that suggest potential cross-regulation of some miRNAs with these key mRNA targets. Finally, we show that differentiation of FTSJ1-depleted human neural progenitor cells into neurons displays long and thin spine neurites compared with control cells. These defects are also observed inDrosophilaand are associated with long-term memory deficits. Altogether, our study adds insight into FTSJ1 pathologies in humans and flies by the identification of novel FTSJ1 targets and the defect in neuron morphology.

The functional roles of S‐adenosyl‐methionine and S‐adenosyl‐homocysteine and their involvement in trisomy 21

“…Mutations of FTSJ1 gene are associated to a X-linked recessive inheritance intellectual developmental disorder (XLID9) characterized by moderately to severely impaired intellectual development and eventually delayed motor development, seizures, and/or behavioral problems. 52 SAM can also bind to certain RNA structures called riboswitches deriving from untranslated mRNA regions and controlling transcription or translation through the complex of RNA structure with SAM and without proteins. This structure binds mRNA and negatively regulate its expression.…”

Exploring the brain epitranscriptome: perspectives from the NSAS summit

“…To unravel the intricate “epitranscriptome” as an additional layer of the biological system, a future large-scale human cohort study is indispensable for comprehensive exploration. Additionally, the use of disease models such human NPCs ( Brazane et al, 2023 ) and iPSC-derived organoid systems, in combination with mouse and other models with loss-of-function for the writers/erasers/readers of various RNA modifications, will provide unprecedented insights into the roles of RNA modifications in brain disease.…”