Novel SLC16A2 mutations impair thyroid hormone transport and drive neurodevelopmental deficits in Chinese patients with allan-herndon-dudley syndrome.

This study elucidates the molecular pathogenesis of neurodevelopmental deficits in Chinese Allan-Herndon-Dudley syndrome (AHDS) patients caused by pathogenic SLC16A2 mutations. 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 + 1G > A). 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–His415 hydrogen bond. Functional studies confirmed significantly reduced SLC16A2 expression (P < 0.05) accompanied by dysregulated thyroid metabolism (increased DIO2 and HR; P < 0.01) and downregulated neurodevelopmental genes (Nrgn and KIF9; P < 0.001). 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 Nrgn promoter thyroid response element, and disruption of the KIF9 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.