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. 270₂71del 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.
Sun et al. (Sun,) studied this question.