One of the most recognizable features of autism is a remarkable diversity of associated behavioral symptoms. Clinicians see autism as a broad spectrum of related problems, and the heterogeneous origins of the disease have plagued scientists, physicians, and families for decades.
In a recent study, researchers at Columbia Vagelos University College of Physicians and Surgeons have taken an important step toward understanding the biological mechanisms that underlie the cognitive and behavioral diversity of autism cases that are triggered by de novo truncating mutations. These mutations occur in parental germline cells and usually severely interfere with the actions of target genes. De novo truncating mutations account for nearly 5% of autism cases and up to 20% of clinically seen cases.
Autism spectrum disorders caused by a single gene disorder represent a relatively simple genetic type of the disease. The anxious observation that scientists have been pursuing for several years is that even when truncating mutations occur in the same gene, they often lead to a wide range of symptoms and patterns of behavior in different children.
The new study found that the severity of autism symptoms often depends on which specific unit of function within a gene is the target of mutations.
“It turns out we didn’t look closely enough at how and where the autism gene is suppressed,” said study director Dennis Vitkup, PhD, associate professor of biology biomedical systems and physiology at Columbia University’s Vagelos College of Physicians.
Human genes, like genes of other eukaryotic species, are made up of individual coding units, called exons, which often come together in different compounds across tissues and stages of development. “On closer inspection, we found that different children in the same exon have similar behavioral symptoms and disabilities,” Vitkup says.
The study was published online in the journal Molecular Psychology.
The same exon, similar symptoms
In the study, Vitkup and colleagues Andrew H. Chiang, Jonathan Chang, and Jiayao Wang analyzed genetic and clinical data from more than 2,500 people with autism, focusing on issues caused by truncating mutations.
When the researchers compared random pairs of children with autism, they found that the nonverbal, verbal, and total IQ scores differed on average by more than 30 points. Children with truncating mutations in the same gene showed similar differences.
However, when the researchers compared autistic children affected by mutations in the same exon of the same gene, their IQs varied by less than ten points, which is comparable to IQ measurement errors. The researchers saw very similar patterns for several other scores indicating children’s communication, social and motor skills.
“This tells us that with truncating mutations associated with autism, it is the exon, and not the whole gene, that often represents a unit of affective action,” Vitkup says.
Harder symptoms associated with frequently used exons
The researchers showed that the severity of autism behavior and psychosis is in line with the likelihood that targeted exons are used in gene transcripts, with more severe effects associated with mutations in it. the more frequently used exons. When mutations occur in the same exon, the resulting sensory level changes are particularly similar, leading to similar clinical outcomes.
Surprisingly, the study also showed that the gene expression changes that cause truncating mutations can be very mild. “Our analysis shows that autism cases can be caused by relatively small changes in total gene dosage, often as little as 15%,” says study’s first author in the study, student Andrew Chiang graduate in the Department of Biomedical Information.
Effects for precision treatment
Detailed treatment may have a significant impact on the study. Diagnostic and prognostic tests can now pay special attention to specific exons that are affected by truncating mutations.
The study also suggests a therapeutic approach for reducing the effects of truncating mutations in autism. “It would be very difficult to develop drugs for thousands of different mutations in hundreds of target autism genes,” Vitkup says, “but our study shows that behavioral anomalies often result from a relative reduction small in dosing of the target gene.These genetic stimuli could be attenuated to at least partially by increasing the expression of an ineffective gene replication using new molecular devices such as CRISPR. “
Source:
Columbia University Irving Medical Center
Magazine Reference:
Chiang, AH, et al. (2020) Exons as units of phenotypic effect for breaking down mutations in autism. Molecular Psychology. doi.org/10.1038/s41380-020-00876-3.