NIH-funded study sheds light on abnormal neural function in rare genetic disorder
A genetic study has identified neuronal abnormalities in the electrical activity of cortical cells derived from people with a rare genetic disorder called 22q11.2 deletion syndrome, according to a press release. The overexpression of a specific gene and exposure to several antipsychotic drugs helped restore normal cellular functioning. The study, funded by the National Institutes of Health (NIH) and published in Nature Medicine, sheds light on factors that may contribute to the development of mental illnesses in 22q11.2 deletion syndrome and may help identify possible targets for treatment development.
22q11.2 deletion syndrome is a genetic disorder caused by the deletion of a piece of genetic material at location q11.2 on chromosome 22. People with 22q11.2 deletion syndrome can experience heart abnormalities, poor immune functioning, abnormal palate development, skeletal differences, and developmental delays. In addition, this deletion confers a 20-30 percent risk for autism spectrum disorder (ASD) and an up to 30-fold increase in risk for psychosis. 22q11.2 deletion syndrome is the most common genetic copy number variant found in those with ASD, and up to a quarter of people with this genetic syndrome develop a schizophrenia spectrum disorder.
“This is the largest study of its type in terms of the number of patients who donated cells, and it is significant for its focus on a key genetic risk factor for mental illnesses,” said David Panchision, PhD, chief of the Developmental Neurobiology Program at the NIH’s National Institute of Mental Health (NIMH). “Importantly, this study shows consistent, specific patient-control differences in neuronal function and a potential mechanistic target for developing new therapies for treating this disorder.”
While some effects of this genetic syndrome, such as cardiovascular and immune concerns, can be successfully managed, the associated psychiatric effects have been more challenging to address. This is partly because the underlying cellular deficits in the central nervous system that contribute to mental illnesses in this syndrome are not well understood. While recent studies of 22q11.2 deletion syndrome in rodent models have provided some important insights into possible brain circuit-level abnormalities associated with the syndrome, more needs to be understood about the neuronal pathways in humans.
To investigate the neural pathways associated with mental illnesses in those with 22q11.2 deletion syndrome, Sergiu Pasca, MD, associate professor of psychiatry and behavioral sciences at Stanford University, Stanford, CA, along with a team of researchers from several other universities and institutes, created induced pluripotent stems cells — cells derived from adult skin cells reprogramed into an immature stem-cell-like state — from 15 people with 22q11.2 deletion and 15 people without the syndrome. The researchers used these cells to create, in a dish, three-dimensional brain organoids that recapitulate key features of the developing human cerebral cortex.
