J. David Sweatt and his colleagues at the University of Alabama at Birmingham carried out a set of mechanistic studies, using laboratory animals and cellular model systems, to understand the role of the TCF4 transcription factor in cognitive and central nervous system function. As a transcription factor, TCF4 directly regulates gene expression in the brain during development and in adulthood.
Some copy number variants associated with autism lead to measurable anatomical defects or exhibit ‘mirrored phenotypes,’ meaning that deletions and duplications of the chromosomal region have opposite anatomical effects. Nicholas Katsanis and his colleagues at Duke University in Durham, North Carolina, are using these observations to investigate which genes within certain copy number variants lead to neurodevelopmental traits.
Neurons are resident cells of our nervous system that are connected to one another through a structure called the synapse. These synaptic connections form the basis of nervous system function. Early in development, synapses form in excess and a subset must be eliminated during a process of synaptic remodeling to achieve the precise wiring diagram characteristic of the mature nervous system. If this process is disrupted, aberrant synaptic connections may lead to severe disruptions in behavior and overall function of the organism.
Certain gene mutations can compromise normal protein functioning, leading to heritable diseases. Although researchers have identified a few genes that are disrupted in some people with autism, for the most part, autism spectrum disorders remain genetically undefined. Mutations in the AUTS2 gene, which most likely result in truncated versions of the AUTS2 protein, have been found in several people who exhibit autism symptoms.
The most common genetic cause of autism is the deletion or duplication of a small region of human chromosome 16. Although these genetic changes account for only about 1 percent of all cases of autism, they predictably result in autism symptoms.
A major obstacle impeding the development of effective treatments for autism is the complexity of factors, such as genetic mutations, epigenetics and environmental influences that contribute to the disorder. However, research over the past few years suggests that ‘hot spots’ of cellular dysfunction are shared across autism spectrum disorders of different etiologies.
Angelman syndrome is a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, seizures and the absence of speech, and it shows a high comorbidity with autism. The syndrome is caused by maternal deletion or mutation of a single gene that encodes the ubiquitin protein ligase E3A (UBE3A). The paternal copy of UBE3A is silenced in neurons, and therefore the loss of maternal UBE3A results in a complete absence of the protein in most areas of the brain. UBE3A is an enzyme that targets proteins for degradation, a process that maintains normal functioning within cells.
Despite tremendous efforts to genetically and phenotypically characterize individuals with autism, we are still at the earliest stages of understanding how autism occurs. The vast majority of individuals with autism have mutations in one copy of each of multiple genes (heterozygous mutations), and these mutations interact with each other in ways that we do not yet understand.
Perturbed neuronal arborization, or branching, and defects in long-range connectivity are likely to be shared mechanisms in many forms of severe autism. Neurotrophic factors (proteins that play a role in the growth and maintenance of neurons) and their cognate receptors, such as brain-derived neurotrophic factor (BDNF) and TrkB, respectively, govern the development of neuronal circuitry, in part, through signaling at the level of intracellular organelles known as endosomes. The protein NHE6 localizes within the cell membranes that form endosomes. Moreover, through its role in mediating the transport of protons (H+) out of endosomes in exchange for the import of sodium (Na+) ions, it contributes to modulating endosome acidity.
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by impairments in social interaction and communication, and restricted, stereotyped behaviors that manifest in early childhood. Research findings have identified widespread changes in the immune system in children with autism.