Anna Bieluszewska, Phillip Wulfridge, Kuo-Chen Fang, Yan Hong, Tomoyo Sawada, Jennifer Erwin, Hongjun Song, Guo-Li Ming, Kavitha Sarma
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引用次数: 0
Abstract
Chromatin regulators are frequently mutated in autism spectrum disorders, but in most cases how they cause disease is unclear. Mutations in the activity dependent neuroprotective protein (ADNP) causes ADNP syndrome, which is characterized by intellectual deficiency and developmental delays. To identify mechanisms that contribute to ADNP syndrome, 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 truncated ADNP proteins, which displayed aberrant subcellular localization. Gene expression analyses revealed widespread transcriptional deregulation in all tested mutants. Interestingly, mutants that show presence of 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 and perhaps also in other ASDs where mutations result in presence of truncated proteins.
期刊介绍:
Molecular and Cellular Biology (MCB) showcases significant discoveries in cellular morphology and function, genome organization, regulation of genetic expression, morphogenesis, and somatic cell genetics. The journal also examines viral systems, publishing papers that emphasize their impact on the cell.