Nicholas Katsanis, Ph.D., Jean and George Brumley Jr. M.D., Professor of Developmental Biology, and Professor of Pediatrics and Cell Biology (both at Duke University Medical Center, explained:
"In medical research, we need to dissect events in biology so we can understand the precise mechanisms that give rise to neurodevelopmental traits. We need expert scientists to work side by side with clinicians who see such anatomic and other problems in patients, if we are to effectively solve many of our medical problems."
Although the team knew that a region of chromosome 16 contributes to autism and schizophrenia, they discovered that alterations within this region are also associated to changes in a newborn's head size.
According to the researchers, the region had large deletions and duplications in DNA, making it harder to address the problem, the authors explained.
Katsanis, who is also director of the Duke Center for Human Disease Modeling said:
"Interpretation is harrowingly hard," because a duplication of DNA or missing DNA normally involves multiple genes.
It is very difficult to go from 'here is a region with many genes, sometimes over 50' to 'these are genes that are driving this pathology'.
There was a light bulb moment. The area of the genome we were exploring gave rise to reciprocal (opposite) defects in terms of brain cell growth, so we realized that overexpressing a gene in question might give one phenotype - a smaller head, while shutting down the same gene might yield the other, a larger head."
The team inserted a common duplication area of human chromosome 16 known to contain 29 genes into zebrafish embryos in order to identify which might cause a small head (microcephaly) in the fish. The researchers then suppressed the same gene set to determine whether any caused a large head (macrocephaly) in the fish. They knew that deletion of the region that contained these 29 genes occurred in 1.7% of children with autism.
"Now we can go from a genetic finding that is dosage-sensitive and start asking reasonable questions about this gene as it pertains to neurocognitive traits, which is a big leap.
Many human conditions have anatomical features that are also related to genetics. There are major limitations in studying autistic or schizophrenia behavior in zebrafish, but we can measure head size, jaw size, or facial abnormalities."
The scientists found that a single gene, called KCTD13, is responsible for determining head size in the fish. The gene works by regulating the production and destruction of new brain cells.
"This gene contributes to autism cases, and probably is associated with schizophrenia and also childhood obesity.
Once you have the protein, you can start asking valuable functional questions and learning what the gene does in the animal or human."
According to the researchers, hundreds, if not thousands of such chromosomal deletions and duplications have been identified in individuals with a wide variety of clinical problems, particularly in those suffering from neurodevelopment disorders.
"Now we may have an efficient tool for dissecting them, which gives us the ability to improve both diagnosis and understanding of disease mechanisms."
Findings from this study indicate that KCTD13 is a major contributor to some cases of autism, and also highlights the synergistic action of this gene with two other genes in the region, named MVP and MAPK3.
Written by Grace Rattue