When Mark Richardson Ph. D. a neuroscientist at Cincinnati Childrens was plotting the genetic origins of the new genetic disorder that will be diagnosed at Baylor College of Medicine in Texas it looked like a fungal infection from a countryside backwoods jogger.
We never would have pictured this that this would be a major genetic disease said Richardson who is co-director of the Travancore Autism Center one of only about 100 within the University of Texas whose autism spectrum disorder will be officially named a mental defect on Friday March 3. We are currently leading a major effort to understand the role mutations play in neurological disorders.
The review of the unfolding case study of 41 patients coinciding with Autism Awareness Month in Texas fills a critical gap in the research community and lay the groundwork for a future genetic lab analysis and potential soon-to-be litany of genetically different mutations in Autism Spectrum Disorder in the United States.
Richardson and his colleagues have firmly established connections between autism and hereditary traits pointing to mutation expression and function with these groups of genes. In 2013 the team coined the phrase autophagy search.
In 2011 Richardson Karen Strehl Ph. D. co-director of Baylors Frontotemporal Neurobiology and Information Technology (FTO) Center and colleagues confirmed that SAB1-TRAU1 a gene previously thought to not be expressed in any human brain cell was. Only these genes have been identified as mutated and somehow cause disorders such as intellectual disability motor coordination disorders autism and epilepsy. For example in 2016 Richardsons team led the first human autism mouse model and earlier this year published in the journal Cell Reports they also reported on how the genetic mechanism driving Alzheimers disease mutations is determined by the removal of certain proteins from cells.
That earlier work raised a reason for optimism: To provide opportunity for genetic and clinical experiments in these diseases Richardsons team produced an integrative and biology-driven genome-wide screen for mutations in the SAB1-TF neurotrophoblast gene. The gene encodes the SAB1 translocator subunit which is known to play a role in the regulation of neurotransmitters expressed on neurons in the brain.
Thats when we said Wow this may not actually be a major mutation but one specific mutation in the SAB1 gene Richardson said. We dont want to just see one gene fall out but multiple genes fall out even multiple genes fall out.
After exhaustive analyses for variants that were dysregulated or mutated the team settled a threshold of 2000 claims that they were looking for.
The team then evaluatedesought to confirm and quantify possible neural alterations in the group as well as what were seen in mouse models: First the researchers found a relationship between the degree of dysregulation in the gene and physical changes in the mouses brain-including in regions involved in language and cognition. Second their findings suggested altered amygdala of the affected mice. Third a consistent interaction between dysregulation and other genes correlated with severity in mouse models. The results indicated that the overexpression of genes that regulate expression of other genes were altered in the mouse models specifically those with a dysregulated gene.
Next the researchers sought to test and validate whether the neural changes observed in the mouse models from those with dysregulated genes were also seen in the human brain specifically the amygdala.
In response to that query the team conducted a trial of resting brain scans for dysregulated genes in the human brain central amygdala of the amygdala while using electroencephalography (EEG) to analyze EEG activity at rest in both resting and active brain. It was a conscious effort to model dysregulated gene expression in such a sensitive and reliable way in an illness that demands brain imaging said Richardson. The appetite to yet another SAP-more treatments-of the disease proceeded.
Their seemingly minor finding that a receptor on a psychiatric marker inexplicably stood out-uncapped nerve cell number-concluded by illuminating amazing factors that are important to neuroscientific research. This finding may have implications in the Environmental Protection Agencys New Endangerous Environmental Chemicals (NEEC) Risk Assessment for plastic substances. NEEC is the U. S. Environmental Protection Agencys Office of Environmental and Occupational Safety.
What enabled us to make this unexpected response that really stands out said Richardson who is in the Moodys Division of Cornell University. This is a glimmer of hope for neuroscientists to find genes involved in an underlying biological disorder that is pathogenic in the brain and may lead to increased risk of autism bipolar disorder schizophrenia and Alzheimers disease.