The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.

Figure 1. Current experimental approaches to determining genetic etiologies for ASD.

These approaches include whole-genome analyses that identify disorder-related sequences or CNVs in genes that exhibit preferential inheritance patterns or de novo appearance in individuals with ASD. The current challenges include the translation of these genetic findings to define the biological consequences of the variations, to determine the influence on defined clinical phenotypes of ASD, and eventually to design new intervention strategies.

Figure 2. The MET RTK signaling pathway and genes implicated in ASD risk.

Intracellular signaling of MET and other RTKs occurs via the PI3K or ERK1/2 pathways. Rare mutations and CNVs (which are both designated by ‡) or associated common alleles (which are designated by *) have been identified in individuals with ASD in seven genes encoding proteins involved in these signaling pathways. Of note, an association between common MET variants and ASD has been reported for five independent family cohorts. PLAUR and SERPINE1 associations with ASD have been determined in single, large family cohorts (>600 families). Ras disruption in Smith-Lemli-Opitz syndrome is due to alterations in cholesterol biosynthesis (which is designated by †). Also depicted are other proteins that interact with the MET signaling pathway, such as semaphorins, plexins, and other RTKs. MET can signal via the PI3K and the ERK pathway. RTKs, including MET, are involved in key neurodevelopmental processes, including axon guidance, synapse formation, and plasticity. Convergence of many different genetic etiologies suggests that risk via ERK/PI3K signaling may be common in ASD. Risk, severity of the pathophysiology (i.e., intellectual disability), and disorder heterogeneity may relate to differences in genetic and epigenetic points of entry to the pathways. Thus, the impact due to genetic risk, via regulators of ligand availability or RTKs such as MET, may be less severe than the more severe clinical impact (i.e., intellectual disability) from disruption downstream along the intracellular signaling pathways. c-cbl, E3 ubiquitin-protein ligase c-Cbl; rheb, Ras homolog enriched in brain; RSK, ribosomal S6 kinase; uPA, urokinase plasminogen activator.

Figure 3. Contributions of the PI3K pathway to ASD risk threshold.

The degree of genetic risk is indicated by shading, with darker color indicating increased risk. The model presents common functional variants in the MET, PLAUR, and SERPINE1 genes that, along with other genetic risk alleles, contribute to risk of developing ASD. Adaptive processes may prevent presentation of ASD, but additional environmental factors or the presence of multiple risk alleles result in idiopathic (multiple genes, each having a small effect) ASD. Mutations further down the PI3K pathway result in syndromic disorders, with penetrance and phenotype severity determined by a decreasing availability of adaptive processes.