GRIP1 Gene Linked to Severity of Social Dysfunction in Autism
Autism appears to be a genetically driven disorder that interrupts appropriate communication between brain synapses at varying degrees. Researchers have identified several hundred genetic variations that are linked to autism risk, including a gene known as GRIP1 or glutamate receptor interaction protein 1.
Abnormal Glutamate Functioning Linked to Autism Spectrum Disorders
GRIP1, found on chromosome 10, regulates how fast receptors travel to a cell’s surface where they are activated by glutamate, a chemical that allows the neurons to communicate with one another. Previous studies have also linked abnormal glutamate functioning to disorders such as Fragile X syndrome and tuberous sclerosis, which share some symptoms with autism.
In the latest study of GRIP1, conducted by researchers at Johns Hopkins University School of Medicine, scientists marked the receptor proteins in both normal and mutated mice with green fluorescence and added a chemical that promotes “disappearance” deep inside a cell and timed the rates at which they disappeared – leaving the cell unable to respond to signals from other cells.
With the GRIP1 mutant neurons, the receptors recycled to the surface twice as fast as normal neurons. “If the receptors are recycling faster, the number of receptors on the surface is greater, so the cells are more sensitive to glutamate,” explains Dr. Richard Huganir PhD, Professor and Director of the Department of Neuroscience. “The quicker the recycling, the more receptors on the surface and the stronger the excitatory transmission” which reflects an imbalance in synapse signaling.
The team noted that mice lacking the GRIP protein variants spent twice as much time interacting with other mice versus those mice that had the abnormal genome. Those mice tended to spend more time with inanimate objects.
Researchers then tracked two versions of the gene in families that had two autistic brothers and correlated their scores on standard diagnostic tests that assessed social interaction. In one family, the brother with two copies of the GRIP1 mutant variety scored lower on social interaction tests than his brother who only had one copy. Interestingly, the boys’ mother, not diagnosed as autistic, had a history of restricted interests, poor eye contact and repetitive behavior – and she had one copy of the GRIP1 variant.
“The GRIP1 variants we studied are not sufficient to cause autism by themselves, but appear to be contributing factors that can modify the severity of the disease,” says Tao Wang, M.D., Ph.D., assistant professor of Genetic Medicine and study co-author. “GRIP1 mutations seem to contribute to social interaction deficits in the patients we studied.”
The study, published in the Proceedings of the National Academies of Sciences, was supported in part by research grants from Autism Speaks Foundation and the National Institute of Child Health and Human Development.
Journal Reference: Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism, Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4920-5. Epub 2011 Mar 7.