Protein Interactome Reveals Converging Molecular Pathways Among Autism Disorders

Abstract

To uncover shared pathogenic mechanisms among the highly heterogeneous autism spectrum disorders (ASDs), we developed a protein interaction network that identified hundreds of new interactions among proteins encoded by ASD-associated genes. We discovered unexpectedly high connectivity between SHANK and TSC1, previously implicated in syndromic autism, suggesting that common molecular pathways underlie autistic phenotypes in distinct syndromes. ASD patients were more likely to harbor CNVs that encompass network genes than control subjects. We also identified, in patients with idiopathic ASD, three de novo lesions (deletions in 16q23.3 and 15q22 and one duplication in Xq28) that involve three network genes (NECAB2, PKM2, and FLNA). The protein interaction network thus provides a framework for identifying causes of idiopathic autism and for understanding molecular pathways that underpin both syndromic and idiopathic ASDs.

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…SMARCA2 encodes a protein that belongs to the FMRP complex, deficient in fragile X syndrome and is involved in a large network of interactions with other ASD related proteins such as TSC1 and NLGN3. 28,29 To test the hypothesis that additional variants in SMARCA2 and/or DOCK8 contribute to autism, we sequenced the exons of these two genes in the patient with the 9p deletion, but no rare, possibly pathogenic variants were identified. Recently, heterozygous nonsynonymous mutations or partial deletions in SMARCA2 were identified as the cause of Nicolaides-Baraitser syndrome, an autosomal dominant condition with syndromic ID.…”

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

“…Moreover, mice lacking the polysialyltransferase that regulates NCAM PSA in adulthood (PST or ST8SiaIV) also exhibit social deficits and these become even more severe in mice lacking the developmental enzyme (STX or ST8SiaII) (Calandreau et al, 2010). This observation is also of interest in that may the abnormal expression of autism susceptibility genes have been associated with cell adhesion molecules involved in synapse signaling and glycosylation events (Pinto et al, 2010;Ye et al, 2010;Sakai et al, 2011).…”

Insights into the Genetic Foundations of Human Communication

“…New monogenic ID and ASD syndromes are continuously being discovered, and some of these reveal specific molecular links between ID/ ASD and more language-specific disorders. Two recentlydiscovered syndromes are caused by haploinsufficiency of transcription factors that are known to directly interact with FOXP2 (Li et al 2004;Sakai et al 2011;Deriziotis et al 2014). One syndrome results from mutations of FOXP1, a paralog of FOXP2 which shows partially overlapping expression in brain regions including the striatum (Ferland et al 2003).…”

“…Several studies have identified putative members of this FOXP2 molecular network (Coutinho et al 2011;Clovis et al 2012;Shi et al 2013;Spiteri et al 2007;Vernes et al 2007;Konopka et al 2009;Vernes et al 2011;Li et al 2004;Chokas et al 2010;Sakai et al 2011;Zhou et al 2008). In previous sections we have discussed the relationship of the FOXP2 target, CNTNAP2, and the FOXP2 interacting proteins, TBR1 and FOXP1, to communication disorders.…”