Environmental and genetic risk factors are both known to contribute to autism. Theo D. Palmer and his colleagues at Stanford University in California studied how a relatively common genetic risk factor may make developing fetuses more vulnerable to the mother’s immune response to illness or infections during pregnancy.
Autism spectrum disorders are generally described as disorders of brain development that present early in life and whose phenomenology is a manifestation of the cumulative results of an atypical developmental trajectory. However, some children develop an autism-like condition after an extended period of typical development. The most extreme, late-onset cases of this regressive form of autism have been described by the diagnostic category Childhood Disintegrative Disorder (CDD).
Douglas Wallace and his colleagues at the Children’s Hospital of Philadelphia tested the hypothesis that partial defects in mitochondrial bioenergetics are important factors in the etiology of autism. The mitochondria are assembled from genes coded by the maternally inherited, thousand-copy mitochondrial DNA (mtDNA) in addition to the one to two thousand nuclear DNA (nDNA) coded genes that affect mitochondrial structure and function. In addition to generating most of cellular energy by oxidative phosphorylation (OXPHOS), the mitochondria regulate cellular oxidation-reduction status, calcium ion levels, apoptosis, intermediary metabolism and, through high-energy mitochondrial intermediates, the cellular signal transduction pathways and the epigenome.
James Rand and his colleagues at the Oklahoma Medical Research Foundation studied the functions of a post-synaptic adhesion protein called neuroligin and the consequences of mutations affecting this protein. There are four neuroligin-encoding (NLGN) genes in people, and mutations disrupting NLGN3 and NLGN4 are associated with a subset of autism cases. Rand and his group used the roundworm C. elegans because of its simple nervous system and its ease of genetic and molecular analysis. Many studies have demonstrated that C. elegans neuronal proteins are structural and functional homologs of the corresponding mammalian proteins.
Multiple nucleotide variants in the coding sequence of the EFR3A gene are associated with autism, but the protein's function is not well understood. Pietro De Camilli and his colleagues at Yale University have used their expertise in neuronal signaling and cell biology to uncover the role of EFR3A in autism.
During the first few years of life, children rapidly incorporate signals from their surrounding enviroment into what will become their behavioral, social and language repertoires. This experience-dependent sculpting of brain circuits occurs during distinct critical periods, and it is during these periods that symptoms of autism spectrum disorders become evident. Many of these symptoms indicate a disruption in sensory processing.
Four independent studies have uncovered different autism-associated variants in the gene contactinassociated protein-like 2 (CNTNAP2), making this gene the first to have multiple variants associated with autism. The striking pervasiveness and diversity of the variants suggest that CNTNAP2 plays a crucial role in autism, leading Aravinda Chakravarti and his colleagues to embark on a detailed study of the gene.
Two central challenges in autism research are defining specific neuronal abnormalities from genetic and environmental contributions and establishing preclinical models with human cells to test potential therapies. Autism is believed to be a disorder of neurodevelopment with a strong genetic liability. A large number of genetic risk loci have been identified by genetic association studies. Various animal models are being developed to explore the function of these genes in regulating neuronal development.
Loss-of-function mutations in the UBE3A gene give rise to Angelman syndrome, a neurodevelopmental disorder characterized by absence of speech, a happy demeanor, cognitive delay, motor deficits and seizures. Chromosomal alterations in 15q11-13, the region that includes UBE3A, have been linked to autism. UBE3A encodes an enzyme that targets a subset of cellular proteins for degradation. Elevated levels of several neuronal proteins have previously been observed in the absence of UBE3A.
Rudolf Jaenisch and his colleagues sought to create a novel platform for studying autism spectrum disorders in human cells. Using cutting-edge gene-editing technology, they introduced mutations into genes that are known to cause disorders on the autism spectrum, such as Rett syndrome and fragile X syndrome. This allowed them, for the first time, to investigate the effects of pathogenic mutations on the morphology, electrophysiology and intracellular signaling of human neurons in culture.