Pitt-Hopkins综合症和人类自闭症谱系障碍（ASD）共享的髓鞘相关转录组谱，由美国约翰.霍普金斯大学医学院Brady J. Maher和Andrew E. Jaffe团队合作取得。这一研究成果在线发表在2020年2月3日的国际学术期刊《自然—神经科学》上。

研究人员分析了五种Pitt-Hopkins综合征(PTHS)小鼠模型中脑转录的变化，这是一种由TCF4基因而非TCF7L2基因突变所引起的ASD。通过差异表达基因（DEGs）分析研究人员发现少突胶质细胞（OL）的失调，并且也在另外两个ASD小鼠模型（Pten^{m3m4 / m3m4}和Mecp2^tm1.1Bird）中证实了这一点。在PTHS小鼠模型中存在OL数量和髓鞘形成细胞的自主减少，这在功能上证实了OL转录特征。研究人员还将PTHS小鼠模型DEG与尸检得到的人类突发性ASD脑RNA测序数据进行了整合，发现存在重叠DEG和常见髓鞘相关途径的显著富集。值得注意的是，来自ASD小鼠模型的DEG和减少的去卷积OL数量将人类突发性ASD病例与三个对照的尸检脑数据集区分开来。这些结果提示OL的生物学破坏可能是造成ASD的一种细胞机制。

据悉，自闭症谱系障碍具有遗传异质性，并具有明显的症状，这是由常见途径失调所致。

附：英文原文

Title: A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder

Author: BaDoi N. Phan, Joseph F. Bohlen, Brittany A. Davis, Zengyou Ye, Huei-Ying Chen, Brent Mayfield, Srinidhi Rao Sripathy, Stephanie Cerceo Page, Morganne N. Campbell, Hannah L. Smith, Danisha Gallop, Hyojin Kim, Courtney L. Thaxton, Jeremy M. Simon, Emily E. Burke, Joo Heon Shin, Andrew J. Kennedy, J. David Sweatt, Benjamin D. Philpot, Andrew E. Jaffe, Brady J. Maher

Issue&Volume: 2020-02-03

Abstract: Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.

DOI: 10.1038/s41593-019-0578-x

Source: https://www.nature.com/articles/s41593-019-0578-x