Transl Psychiatry. 2025 Oct 10;15(1):391. doi: 10.1038/s41398-025-03616-9.
ABSTRACT
This study aimed to explore the neurobiological mechanism underlying intellectual disability (ID) in patients with Waardenburg syndrome (WS) identified in a Chinese family. The proband was initially diagnosed with severe ID and then 10 of the 11 extended family members underwent further medical examinations (I-1 declined to be examined). Whole-exome sequencing (WES) revealed that 6 (II-1, II-3, III-1, III-4, III-5, and III-6) of the members share the pathogenic variant of c.230 C > G of SNAI2 (also known as SLUG), a causing gene of WS. All of the mutation carriers in the third generation presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss and heterochromia iris, which are considered features of WS. Animal experiments with Snai2-/- (also known as Slugh-/-) mice were used to model the WS patients. All the Snai2-/- mice exhibited cognitive impairment, depigmented hair, and lower neural activity in the brain. The bulk RNA-seq revealed transcriptional alterations related to energy metabolism, cell growth and differentiation. The snRNA-seq and spatial transcriptomics further showed a developmental arrest of astrocyte lineage cells in the Snai2-/- mice. Moreover, Snai2-/- mice presented higher expression of genes related to IFN-α, IFN-γ, and IL-6, reduced Fos+ and GFAP+ cells, as well as low expression of EAAT1 in the hippocampus and frontal cortex. These data demonstrate that Snai2 deletion leads to developmental arrest of astrocyte lineage cells thereby impairing neuron-astrocyte interactions, ultimately resulting in cognitive impairment as seen in the WS patients.
PMID:41073431 | DOI:10.1038/s41398-025-03616-9
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