Genetic analyses of copy-number variants, single-nucleotide variants and chromosomal translocations, as well as co-expression network analysis of postmortem brain tissue, have implicated the human RBFOX1 gene in autism spectrum disorders (ASD) and associated co-morbidities.
Anthony Wynshaw-Boris and his colleagues are investigating the hypothesis that a subset of individuals with autism spectrum disorders (ASD) (approximately 25-30 percent) display early brain overgrowth. His lab has recently produced two relevant models that recapitulate important aspects of early brain overgrowth in ASD. First, the team produced a mouse model deficient for DVL1 and DVL3 (Dvl1/3 +/– mutants). These mice display adult social behavior abnormalities associated with transient embryonic brain enlargement during the time of deep-layer cortical formation. Second, they generated human induced pluripotent stem cell (iPSC) models by reprogramming fibroblasts obtained from individuals with ASD who had early head overgrowth and unaffected control individuals with normal head circumference. Neuronal progenitor cells (NPCs) derived from ASD iPSC lines displayed enhanced proliferation compared to control NPCs. In both the Dvl 1/3 mutant mouse model and the human iPSCs, the observed phenotypes were caused by down-regulation of beta-catenin activity and its direct target BRN2. This remarkable conservation of beta-catenin and BRN2 signaling disruption in different models of ASD suggests that multiple variants contributing to ASD may converge on common pathways.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is the result of interplay amongst hundreds of genes. Even though researchers have implicated dozens of genes in ASD to date, there is still much more to be understood. A few network-based ASD gene discovery algorithms have been developed with the following goals: (1) speeding up the gene discovery process by using the guilt-by-association principle, and (2) understanding affected functionalities by analyzing genes and links in predicted clusters. Fundamentally, these algorithms rely on the assumption that ASD risk genes are part of a functional gene network. However, the definition of a gene network in these analyses is a single, flat and static network. This approach disregards the temporal dimension in the development and differentiation of neurons and brain tissue. The assumption of ASD genes being part of a functional network is reasonable. However, the functional clustering of genes is bound to evolve over time and more than likely to have a cascading effect on future associations.
Fragile X syndrome is the most common heritable form of intellectual disabilities and a leading genetic cause of autism, caused by mutation of the gene encoding FMRP. Researchers have not found an effective treatment for the cognitive and social interaction deficits associated with fragile X. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, proliferation, survival, translation and the actin cytoskeleton. mTOR is a kinase that integrates external cues and forms two distinct complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2), which have distinct functions and downstream targets. Whereas mTORC1 is a central regulator of cap-dependent translation, mTORC2 is a pivotal regulator of the actin cytoskeleton, spine structure and memory. Dysregulation of mTORC1 in fragile X syndrome is well established, but a role for mTORC2 is still unclear.
Aberrant PI3K/PTEN signaling during brain development has emerged as a key determining factor in autism spectrum disorders (ASDs). Germline mutations in PTEN have been found in 20 percent of individuals with ASD and severe macrocephaly. Indeed, there is a growing consensus that deregulation of PI3K/PTEN signaling signifies a convergent pathway for behavioral abnormalities associated with various neurodevelopmental disorders.
Individuals with autism spectrum disorder (ASD) have structural and functional deficits of the temporoparietal junction (TPJ), as well as problems with social and executive functions, which are associated with the TPJ. Michael Graziano and his colleagues recently showed that the TPJ is a convergence point for two major brain networks with implications in ASD: the frontoparietal control network (FPN) and the default mode network (DMN)[ref]Ingelström K.M. et al. J. Neurosci. 35, 9432-9445 (2015) PubMed[/ref]. To isolate these network nodes, they used a data-driven parcellation technique that allows spatial separation of partially overlapping functional processes.
The brain abnormalities that lead to autism spectrum disorder (ASD) remain poorly understood. Convergent data from clinical and basic science research studies suggest that abnormalities in brain interneurons may contribute to the condition. These interneurons are also implicated in tics and Tourette syndrome, which are frequently comorbid with ASD.
Many of the mutations known to be associated with autism spectrum disorder (ASD) affect protein complexes that support the development and function of synapses. SHANK3 encodes a postsynaptic scaffolding protein that is essential for synaptic communication, and disruptions in the SHANK3 gene have been implicated in ASD. In particular, mutations of the SHANK3 gene or deletion of the terminal end of chromosome 22 (i.e., 22q13.3) encompassing SHANK3 have been shown to lead to Phelan-McDermid syndrome (PMS), in which individuals display symptoms of ASD. The 22q13.3 region also encompasses genes encoding protein kinases and histone deacetylases. This raises the possibility that post-translational modifications of SHANK3 may function in the regulation of its gene expression patterns, and may also influence behavioral phenotypes seen in PMS.
Autism spectrum disorders (ASD) are frequently associated with immune dysregulation. Peripheral immune responses and microglial function have been the major focus in the field. However, recent studies have suggested that neurons are also able to use their own innate immune receptors, including toll-like receptors (TLRs), to detect the danger signals derived from both endogenous cells and pathogens.
Individuals with autism spectrum disorder (ASD) show persistent deficits in social communication and interaction. Reduced attention to social stimuli, including the human face, is thought to at least partially explain these deficits. Males are at least four times more likely to be diagnosed with ASD than females, but the biological basis of this gender discrepancy is not understood. If gender differences in face selectivity and processing exist, this may at least partially explain the gender bias seen in ASD.