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Genetic analysis of three Han Chinese patients with severe intellectual disability and global developmental delay identified two novel truncating mutations (c.1093del [p.A365Lfs35] and c.270_271del [p.G91Lfs28]) and a hemizygous de novo splice-site mutation (c.1026\u2009+\u20091G\u2009&gt;\u2009A). Structural modeling predicted that the c.1093del variant causes C-terminal truncation of transmembrane helix 12, which is likely to disrupt the T3-binding pocket by impairing the critical Arg445\u2013His415 hydrogen bond. Functional studies confirmed significantly reduced SLC16A2 expression (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05) accompanied by dysregulated thyroid metabolism (increased\n                    <jats:italic>DIO2<\/jats:italic>\n                    and\n                    <jats:italic>HR<\/jats:italic>\n                    ;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01) and downregulated neurodevelopmental genes (\n                    <jats:italic>Nrgn<\/jats:italic>\n                    and\n                    <jats:italic>KIF9<\/jats:italic>\n                    ;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). Mechanistically, MCT8 deficiency impaired cerebral thyroid hormone uptake, driving synaptic and axonal defects through dysregulation of both transcriptional and cytoskeletal programs: T3-dependent transcriptional suppression via inactivation of the\n                    <jats:italic>Nrgn<\/jats:italic>\n                    promoter thyroid response element, and disruption of the\n                    <jats:italic>KIF9<\/jats:italic>\n                    signaling axis. These findings establish novel genotype-phenotype correlations in Chinese AHDS patients and provide a mechanistic framework for understanding the neurodevelopmental consequences of impaired thyroid hormone transport, with patient-derived iPSCs serving as a valuable resource for future therapeutic development.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-40703-3","type":"journal-article","created":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T08:18:00Z","timestamp":1772353080000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel SLC16A2 mutations impair thyroid hormone transport and drive neurodevelopmental deficits in Chinese patients with allan-herndon-dudley syndrome"],"prefix":"10.1038","volume":"16","author":[{"given":"Xiaoang","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longlong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuqin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,1]]},"reference":[{"key":"40703_CR1","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1016\/S0140-6736(04)17226-7","volume":"364","author":"EC Friesema","year":"2004","unstructured":"Friesema, E. 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