PT - JOURNAL ARTICLE AU - Mira Brazane AU - Dilyana G Dimitrova AU - Julien Pigeon AU - Chiara Paolantoni AU - Tao Ye AU - Virginie Marchand AU - Bruno Da Silva AU - Elise Schaefer AU - Margarita T Angelova AU - Zornitza Stark AU - Martin Delatycki AU - Tracy Dudding-Byth AU - Jozef Gecz AU - Pierre-Yves Plaçais AU - Laure Teysset AU - Thomas Préat AU - Amélie Piton AU - Bassem A Hassan AU - Jean-Yves Roignant AU - Yuri Motorin AU - Clément Carré TI - The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance AID - 10.26508/lsa.202201877 DP - 2023 Apr 01 TA - Life Science Alliance PG - e202201877 VI - 6 IP - 4 4099 - https://www.life-science-alliance.org/content/6/4/e202201877.short 4100 - https://www.life-science-alliance.org/content/6/4/e202201877.full SO - Life Sci. Alliance2023 Apr 01; 6 AB - 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 novel FTSJ1 pathogenic variant from an X-linked intellectual disability patient. Using blood cells derived from this patient and other affected individuals carrying FTSJ1 mutations, 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 in Drosophila and 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.