RT Journal Article
SR Electronic
T1 Defects of myelination are common pathophysiology in syndromic and idiopathic autism spectrum disorder
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 128124
DO 10.1101/128124
A1 Phan, BaDoi N.
A1 Page, Stephanie Cerceo
A1 Campbell, Morganne N.
A1 Bohlen, Joseph F.
A1 Thaxton, Courtney L.
A1 Simon, Jeremy M.
A1 Burke, Emily E.
A1 Shin, Joo Heon
A1 Kennedy, Andrew J.
A1 Sweatt, J. David
A1 Philpot, Benjamin D.
A1 Jaffe, Andrew E.
A1 Maher, Brady J.
YR 2017
UL http://biorxiv.org/content/early/2017/05/11/128124.abstract
AB Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs identified oligodendrocyte dysregulation that was subsequently validated by decreased protein levels. We further showed significant enrichment of myelination genes was prevalent in two additional mouse models of ASD (Ptenm3m4/m3m4, Mecp2KO). Moreover, we integrated syndromic ASD mouse model DEGs with ASD risk-gene sets (SFARI) and human idiopathic ASD postmortem brain RNA-seq and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination and oligodendrocyte differentiation. These results from seven independent mouse models are validated in human brain, implicating disruptions in myelination is a common ASD pathophysiology.