Syngap1 Gene Mutation Linked To Intellectual Disability, Schizophrenia and Autism

Dr. Gavin Rumbaug Professor (Associate) The Scripps Research Interview with:
Gavin Rumbaug
Professor (Associate)
The Scripps Research Institute

Medical Research: What is the background for this study? What are the main findings?
Response: We have developed a genetic approach that protects animal models against a type of genetic disruption that causes intellectual disability, including serious memory impairments and altered anxiety levels. The findings focus on treating the effects of mutations to a gene known as Syngap1. In our new study, we examined the effect of damaging Syngap1 mutations during development and found that the mutations disrupt a critical period of neuronal growth—a period between the first and third postnatal weeks in mouse models. We found that a certain type of cortical neuron grows too quickly in early development, which then leads to the premature formation of certain types of neural circuits. These findings help explain why genetic treatments in adult mice are not very effective.

Medical Research: What should clinicians and patients take away from your report?

Response: Damaging mutations in Syngap1 that reduce the number of functional proteins are one of the more common causes of sporadic intellectual disability and are associated with schizophrenia and autism spectrum disorder. Early estimates suggest that these non-inherited genetic mutations account for 1-2% percent of these intellectual disability cases. Sporadic intellectual disability affects approximately one percent of the worldwide population, suggesting that tens of thousands of individuals with intellectual disability may carry damaging Syngap1 mutations without knowing it.

It is important to find these patients with these mutations. The only way currently known to identify Syngap1 patients is through gene sequencing. So, if a patient has idiopathic intellectual disability, it’s a good idea to have their genes sequenced. Even if they do not have Syngap1 mutations (there would be about a ~1-2% chance; higher if the patient also has some form of epilepsy), there is a good chance that they will receive information about other mutations that will help with a diagnosis. The next generation of treatments for developmental brain disorders will be heavily influenced by the specific genetic make-up of each patient. Thus, it’s very important to have this genetic information in hand.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: Our model shows that the early developmental period is the critical time to treat this type of genetic disorder, so our hope is that these studies will eventually lead to a therapy specifically designed for patients with psychiatric disorders caused by damaging Syngap1 mutations. As a result of these studies, we are now developing a drug-screening program to look for drug-like compounds that could restore levels of Syngap1 protein in defective neurons. As personalized medicine advances, such a therapy could ultimately be tailored to patients based on their specific genotype.


Syngap1 Haploinsufficiency Damages a Postnatal Critical period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly

Massimiliano Aceti, Thomas K. Creson, Thomas Vaissiere, Camilo Rojas, Wen-Chin Huang, Ya-Xian Wang, Ronald S. Petralia, Damon T. Page, Courtney A. Miller, Gavin Rumbaugh

Biological Psychiatry (Impact Factor: 9.47). 08/2014; DOI: 10.1016/j.biopsych.2014.08.001





Last Updated on March 4, 2015 by Marie Benz MD FAAD