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Transcriptomic analysis uncovers an unfolded protein response in ADNP syndrome

ABSTRACT: Activity dependent neuroprotective protein (ADNP) is mutated in Helsmoortel–Van der Aa syndrome, an autism spectrum disorder characterized by intellectual deficiency and developmental delays. We used induced pluripotent stem cells derived from ADNP syndrome patients as a model to test the effects of syndromic ADNP mutations on gene expression and neurodifferentiation. We found that some ADNP mutations result in retention of the truncated ADNP proteins, which displayed aberrant subcellular localization. Gene expression analyses revealed widespread transcriptional deregulation in all tested mutants. Interestingly, mutants that retain ADNP fragments show ER stress as evidenced by activation of the unfolded protein response (UPR). The mutants showing the greatest UPR pathway activation associated with the most severe neurodifferentiation and survival defects. Our results reveal the potential to explore UPR activation as a new biomarker for ADNP syndrome severity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280293 | GEO | 2025/02/04

REPOSITORIES: GEO

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