Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer’s disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand–receptor and cytokine–cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4, and SNAP25, converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.

鉴于我们最近在死后老年阿尔茨海默氏病脑中发现自闭症谱系障碍（ASD）/智力障碍（ID）基因中的体细胞突变与tauopathy增高相关，因此，重要的是要弄清楚tauopathy是否是ASD / ID萎缩的脑成像结果的基础孩子们。我们专注于活动依赖性神经保护蛋白（ADNP），这是一种普遍的自闭症基因。一名7岁男性杂合子的ADNP从头突变c.2244Adup / p.His559Glnfs * 3的多个死后大脑切片的独特可用性使得能够探索tauopathy，这反映了一个尚未探索的一般机制。受测对象表现出自闭症，轻微运动迟缓，严重智力障碍和癫痫发作。该患者在肝移植后多器官衰竭后死亡。为了与其他ADNP综合征突变进行比较，将来自三个不同患者（包括ADNP p.Arg216 *，p.Lys408Valfs * 31和p.Tyr719 *杂合优势突变）的永生化淋巴母细胞样细胞系和一个对照进行RNA测序。随后进行了许多死后组织的免疫组织化学，高通量基因表达分析。使用与对照大脑和大量数据集的比较。活细胞成像研究了Tau-微管相互作用，可预防tauopathy。发现广泛的儿童脑部tauopathy与多个基因表达变化并行。通过直接突变对Tau-微管相互作用的影响和ADNP活性片段NAP的校正来解释Tauopathy。重大途径变化（经验 将Tyr719 *杂合显性突变和一个对照进行RNA测序。随后进行了许多死后组织的免疫组织化学，高通量基因表达分析。使用与对照大脑和大量数据集的比较。活细胞成像研究了Tau-微管相互作用，可预防tauopathy。发现广泛的儿童脑部tauopathy与多个基因表达变化并行。通过直接突变对Tau-微管相互作用的影响和ADNP活性片段NAP的校正来解释Tauopathy。重大途径变化（经验 将Tyr719 *杂合显性突变和一个对照进行RNA测序。随后进行了许多死后组织的免疫组织化学，高通量基因表达分析。使用与对照大脑和大量数据集的比较。活细胞成像研究了Tau-微管相互作用，可预防tauopathy。发现广泛的儿童脑部tauopathy与多个基因表达变化并行。通过直接突变对Tau-微管相互作用的影响和ADNP活性片段NAP的校正来解释Tauopathy。重大途径变化（经验 活细胞成像研究了Tau-微管相互作用，可预防tauopathy。发现广泛的儿童脑部tauopathy与多个基因表达变化并行。通过直接突变对Tau-微管相互作用的影响和ADNP活性片段NAP的校正来解释Tauopathy。重大途径变化（经验 活细胞成像研究了Tau-微管相互作用，可预防tauopathy。发现广泛的儿童脑部tauopathy与多个基因表达变化并行。通过直接突变对Tau-微管相互作用的影响和ADNP活性片段NAP的校正来解释Tauopathy。重大途径变化（经验P值<0.05）包括100多个基因，包括神经活性配体-受体和细胞因子-细胞因子受体的相互作用，MAPK和钙信号传导，轴突指导和Wnt信号通路。类固醇生物合成基因也观察到变化，表明性别差异。与多个正常基因表达（RNA-seq）数据库相比，在多个死后组织中，通过ADNP突变选择受影响最大的基因进行基因表达分析，确定了Tau（MAPT）基因相关的表达变化。ADNP在小脑ADNP综合征中表现出相对降低的表达，还观察到另外25个基因（占测试基因的50％以上），包括NLGN1，NLGN2，PAX6，SMARCA4和SNAP25，集中在神经系统发育和tauopathy。NAP提供了针对突变的ADNP破坏Tau-微管结合的保护作用。总之，tauopathy可以解释ADNP综合征儿童的脑影像学发现，并可能为tauopathy保护性候选药物（如ASD / ID中的NAP）的开发提供新的方向。