{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n In eukaryotes the conversion of adenosine to inosine at the wobble position (position 34) of transfer RNAs (tRNAs) is an essential modification for accurate decoding of the genetic message. This reaction is mediated by a heterodimeric enzyme complex comprised of the catalytic subunit ADAT2 and the non‐catalytic, regulatory subunit ADAT3."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Although ADAT3 lacks key catalytic determinants, it plays a critical role in substrate recognition by contributing essential structural domains. In particular, its N‐terminal region exhibits a positively charged surface that is important for proper binding and positioning of the tRNA anticodon stem–loop so that ADAT2 can access and deaminate the target adenosine."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Mutations in ADAT3 have been linked to neurodevelopmental disorders—most notably intellectual disability accompanied by distinct dysmorphic and growth features—highlighting the tissue sensitivity to perturbations in tRNA modification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In some cases, pathogenic variants (such as the recurrent V144M mutation) disrupt proper complex formation and lead to decreased wobble inosine levels, with misfolded or aggregated ADAT3 protein that can, at least partially, be alleviated by excess ADAT2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Recent structural studies further reveal that additional regions within ADAT3, notably its C‐terminal elements, engage in blocking the substrate binding surface—thereby ensuring that deamination is strictly governed by ADAT2—and underscore its role in fine‐tuning the deamination reaction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Consistent with these findings, genetic analyses in populations with high consanguinity have identified deleterious ADAT3 variants as a cause of autosomal recessive neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anas M Alazami, Hadia Hijazi, Mohammed S Al-Dosari, et al. 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