Genetic alterations in the tuberous sclerosis complex (TSC) genes, key mediators of protein synthesis, are strongly associated with autism spectrum disorders. Peter Sims and his colleagues at Columbia University Medical Center have developed a novel strategy for cell-type-specific profiling of protein synthesis in the brain, combining ribosome profiling with computational tools.

Mutations in different types of chromatin regulators are associated with autism. In many cases, the mutation disrupts the expression of one copy of the gene or causes a reduction in the expression of the protein.

Findings from autism genetics and the study of animal models of autism suggest that some biochemical pathways are commonly affected in people with autism. The ERK signaling pathway is one such pathway. It mediates the transmission of signals from cell-surface receptors to the cytoplasm and nucleus of cells. ERK signaling regulates diverse cellular processes such as cell proliferation, differentiation and survival; and in the nervous system, it is involved in cognitive function and memory formation.

The human protocadherin (PCDH) gene clusters (PCDH-alpha, -beta and -gamma) encode a family of cell surface proteins that function in cell-to-cell interaction during the development of the brain. Distinct subsets of PCDH genes from all three clusters are randomly expressed in individual neurons, and this results in the generation of enormous single-cell PCDH diversity in neurons that are otherwise identical.

Autism is a heterogeneous brain disorder believed to have both genetic and environmental contributions. Epigenetic mechanisms, including modification of DNA and histones — proteins that store and organize DNA — allow an organism to respond to the environment through changes in gene expression. There is compelling evidence from human genetic association studies and animal models supporting a role for epigenetic dysregulation in autism. In particular, defects in MeCP2 protein function cause Rett syndrome. In this pilot study, Hongjun Song and his colleagues at Johns Hopkins University School of Medicine in Baltimore explored the role of DNA modifications in neuronal gene expression, plasticity, behavior and autism.

Deletions on chromosome 16 at the 16p11.2 region result in autism in a small portion of the general population. Major vault protein (MVP) is a gene within this region.

Mutation in many different genes has been found in individuals with autism, suggesting that there are many different ways to trigger the disorder. James Gusella and his colleagues previously found a number of autism genes whose normal function involves regulating the expression of other genes. This finding led them to consider that some effects of inactivating mutations in different autism genes might produce overlapping changes in overall gene expression. In this way, quite different genetic mutations might lead to autism by disrupting the same neurodevelopmental mechanisms.

Abnormalities in brain development associated with autism may be caused by abnormally high activity of the beta-catenin signaling pathway. Anjen Chenn and his colleagues at the University of Illinois at Chicago, with Eric Courchesne and his colleagues at the University of California, San Diego, aim to test the hypothesis that beta-catenin signaling levels are higher in cells from individuals with autism than in controls.

Several lines of evidence implicate the adult stem cell-containing subependymal zone (SEZ) in autism spectrum disorder (ASD). The goal of this project is to determine if SEZ stem cells and neurogenesis are altered in ASD.

There are two emerging themes in research on genetic factors contributing to autism. First, autism is sometimes associated with small deletions within chromosomes, leaving the affected individual with only one copy of a group of neighboring genes. Second, mutations in proteins at synapses (sites of nerve cell communication) can contribute to autism. Mitchell Goldfarb and his colleagues aim to test whether these two themes can be integrated.