Network Topologies and Convergent Aetiologies Arising from Deletions and Duplications Observed in Individuals with Autism
Figure 3
Distinct duplications and deletions of genes whose proteins interact within the ASD-associated network perturb pathways in the same direction.
Genes duplicated within ASD dn CNVs are indicated with green upwards arrows while those deleted are denoted by blue downwards arrows. Previously identified ASD-Implicated genes found to be disrupted in autism patients are denoted with red downwards arrows. The nature of the interactions/regulations between proteins/molecules are shown with different edge types (see in-figure legend). The ASD-associated network (Figure 2) identifies several deletion/duplication pathway cascades, for example the MAPK3 pathway (see Discussion for additional examples). Here, deletions of the MAPK3 pathway components (i.e. SYNGAP1, SHANK2, KRAS, MAPK3, PAK2, and CREBBP) and duplications of their negative regulators (i.e. FMR1, GDI1, ARHGDIA, CAMK2B, and CAMKK2) found in autistic patients identify converging effects on the MAPK pathway, specifically reduced CREB-dependent transcription [9], [62], [63], [64]. CREB-dependent transcription has been implicated in neuroadaptation [20]. In addition, increased NO* production leads to the inhibition of MAPK1/3 activity [65], which fits well with the observed CNV duplications of both NOS1 and DLG4, the latter gene promoting recruitment of NOS1 [66]. Similarly, duplication of PRKG1, which is up-regulated by NO* and expresses a product that inhibits IP3 production, is predicted to reduced activation of the calcium-releasing IP3-receptor ITPR1 [67], which is in turn found to be deleted.