Researchers led by Dr. Karun Singh at UHN’s Donald K. Johnson Eye Institute (DKJEI) have identified a molecular mechanism underlying brain dysfunction in 15q13.3 microdeletion syndrome.
15q13.3 microdeletion syndrome is a genetic disorder in which an individual is missing a group of genes located on chromosome 15. The syndrome is linked to multiple conditions, including autism spectrum disorder, intellectual disability, epilepsy and schizophrenia.
“Previous studies have identified DNA changes that contribute to 15q13.3 microdeletion syndrome, but we do not know how these changes result in abnormal brain function,” explains Dr. Singh, a Senior Scientist at DKJEI and the senior author of the study. “Because of this gap in our knowledge, there are no targeted treatments for 15q13.3 microdeletion syndrome, or related disorders.”
One gene that has been implicated in the microdeletion syndrome—called OTUD7A—stands out due to its role in neuronal maturation and connectivity and its link to brain disorders such as epilepsy. Although researchers know that OTUD7A is important for brain development, its exact functions are largely unknown.
“We wanted to determine the role of OTUD7A in 15q13.3 microdeletion syndrome at the cellular level—how it influences proteins within neurons to cause brain abnormalities,” says Dr. Brianna Unda, a former postdoctoral researcher in Dr. Singh’s lab and the lead author of the study.
Using experimental models and patient samples, the team compared neurons with and without functional OTUD7A genes. They discovered that neurons defective for OTUD7A did not grow, mature or connect with other neurons as well as those that had an intact gene.
“This finding implicates OTUD7A in neuronal development and suggests that changes in this gene underlie the symptoms of 15q13.3 microdeletion,” says Dr. Unda.
To determine how OTUD7A contributes to neuronal development and function, the researchers developed a technique to map protein interactions within neurons. They found that OTUD7A—the protein encoded by the OTUD7A gene—interacts with Ankyrin-G—a protein that is involved in neuron function and has been linked to autism spectrum disorder and epilepsy.
Based on these results, the team took a deeper look at Ankyrin-G and discovered that neurons with 15q13.3 microdeletion had lower levels of the protein. They also found that the Ankyrin-G that was present was less stable in these cells compared to those without the microdeletion. Importantly, they could reverse the neuronal abnormalities seen in 15q13.3 microdeletion syndrome by restoring normal levels of Ankyrin-G.
These findings suggest a sort of domino effect in which 15q13.3 microdeletion leads to loss of OTUD7A. Loss of OTUD7A then leads to reduced levels and stability of Ankyrin-G. And, finally, loss of Ankyrin-G disrupts neuronal development and connectivity.
This study provides important insights into the disease mechanisms of 15q13.3 microdeletion syndrome and the role of OTUD7A-Ankyrin-G interactions in neuronal development. “This is an exciting step forward for understanding neurodevelopmental disorders. By identifying key molecular pathways involved in microdeletion syndromes, our research is laying a strong foundation that could unlock future targeted therapeutics and preventative strategies,” says Dr. Singh.
This work was supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, the Ontario Brain Institute, the Network of European Funding for Neuroscience Research and the UHN Foundation. Dr. Karun Singh is an Associate Professor in the Department of Ophthalmology and Vision Sciences at the University of Toronto.
Unda BK, Chalil L, Yoon S, Kilpatrick S, Irwin C, Xing S, Murtaza N, Cheng A, Brown C, Afonso A, McCready E, Ronen GM, Howe J, Caye-Eude A, Verloes A, Doble BW, Faivre L, Vitobello A, Scherer SW, Lu Y, Penzes P, Singh KK. Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome. Mol Psychiatry. 2023 Jan 6. doi: 10.1038/s41380-022-01937-5.
Symptoms of 15q13.3 microdeletion syndrome may be different among patients and include intellectual disability, autism spectrum disorder, epilepsy and mental illness. There are currently no specific treatments for this syndrome.