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The ADAT2\/ADAT3 (ADAT) complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3<\/em>, the catalytically inactive subunit of the ADAT2\/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders. Yet, the physiological function of ADAT2\/ADAT3 complex during brain development remains totally unknown.<\/p>\n\n\n\n Here, we investigated the role of the ADAT2\/ADAT3 complex in cortical development. First, we reported 21 neurodevelopmental disorders patients carrying biallelic variants in ADAT3<\/em>. Second, we used structural, biochemical, and enzymatic assays to deeply characterize the impact of those variants on ADAT2\/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. Finally, in vivo<\/em> complementation assays were performed to correlate functional deficits with neuronal migration defects in the developing mouse cortex.<\/p>\n\n\n\n Our results showed that maintaining a proper level of ADAT2\/ADAT3 catalytic activity is essential for radial migration of projection neurons in the developing mouse cortex. We demonstrated that the identified ADAT3<\/em> variants significantly impaired the abundance and, for some, the activity of the complex, leading to a substantial decrease in I34<\/sub> levels with direct consequence on their steady-state. We correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants.<\/p>\n\n\n\n Altogether, our results highlight the critical role of ADAT2\/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenic mechanisms underlying ADAT3-related neurodevelopmental disorders.<\/p>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":" The ADAT2\/ADAT3 (ADAT) complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3, the catalytically inactive subunit of the ADAT2\/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders. Yet, the physiological function of ADAT2\/ADAT3 complex during brain development remains totally unknown. Here, we investigated the role […]<\/p>\n","protected":false},"author":151,"featured_media":14796,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[82],"tags":[],"class_list":["post-15321","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"\n