Bieluszewska Anna, Wulfridge Phillip, Fang Kuo-Chen, Hong Yan, Sawada Tomoyo, Erwin Jennifer, Song Hongjun, Ming Guo-Li, Sarma Kavitha
Genome Regulation and Cell Signaling Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Epigenetics Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mol Cell Biol. 2025;45(4):143-153. doi: 10.1080/10985549.2025.2463892. Epub 2025 Feb 14.
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.
染色质调节因子在自闭症谱系障碍中经常发生突变，但在大多数情况下，它们如何导致疾病尚不清楚。活性依赖神经保护蛋白（ADNP）的突变会导致ADNP综合征，其特征为智力缺陷和发育迟缓。为了确定导致ADNP综合征的机制，我们使用源自ADNP综合征患者的诱导多能干细胞作为模型，来测试综合征性ADNP突变对基因表达和神经分化的影响。我们发现，一些ADNP突变会导致截短的ADNP蛋白，这些蛋白表现出异常的亚细胞定位。基因表达分析显示，所有测试突变体中均存在广泛的转录失调。有趣的是，显示存在ADNP片段的突变体表现出内质网应激，这可通过未折叠蛋白反应（UPR）的激活得到证明。显示出最强烈的UPR途径激活的突变体与最严重的神经分化和生存缺陷相关。我们的结果揭示了将UPR激活作为ADNP综合征严重程度的一种新生物标志物进行探索的潜力，或许在其他因突变导致截短蛋白存在的自闭症谱系障碍中也是如此。
