@article{53d2228273a14492a47a5b4bdcae86fd,
title = "A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder",
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.",
author = "Phan, {Ba Doi N.} and Bohlen, {Joseph F.} and Davis, {Brittany A.} and Zengyou Ye and Chen, {Huei Ying} and Brent Mayfield and Sripathy, {Srinidhi Rao} and {Cerceo Page}, Stephanie and Campbell, {Morganne N.} and Smith, {Hannah L.} and Danisha Gallop and Hyojin Kim and Thaxton, {Courtney L.} and Simon, {Jeremy M.} and Burke, {Emily E.} and Shin, {Joo Heon} and Kennedy, {Andrew J.} and Sweatt, {J. David} and Philpot, {Benjamin D.} and Jaffe, {Andrew E.} and Maher, {Brady J.}",
note = "Funding Information: We are grateful for the vision and generosity of the Lieber and Maltz families, who made this work possible. We thank D.R. Weinberger for his helpful comments and feedback. We thank the Johns Hopkins School of Medicine Microscope Core Facility and specifically L. Roker for generating TEM images of CC used in this study. This work was supported by the Lieber Institute for Brain Development, the Pitt–Hopkins Research Foundation Awards (to B.J.M., B.D.P., C.T., D.S. and A.J.K.), National Institute of Mental Health (NIMH) grant R56MH104593 (to B.J.M.), NIMH grant R01MH110487 (to B.J.M.), a Johns Hopkins PURA grant (to B.N.P.), UPenn Orphan Disease Center Million Dollar Bike Ride grant MDBR-15-108-PH (to B.D.P. and C.T.), NARSAD Young Investigator grant 20653 from the Brain Behavior Research Foundation (to C.T.), National Institute of Neurological Disorders and Stroke grant P30NS045892 (to J.M.S.), National Institute of Child Health and Human Development grant P30HD03110 (to J.M.S.), NIMH grant R01MH104158 (to D.S. and A.J.K.), National Institute of General Medical Sciences training grant T32GM008208 (to B.N.P.) and NIMH training grant T32MH015330 (to B.A.D.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = mar,
day = "1",
doi = "10.1038/s41593-019-0578-x",
language = "English (US)",
volume = "23",
pages = "375--385",
journal = "Nature neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "3",
}