Gephyrin - a scaffolding protein - bolsters understanding of the genetic roots of neuropsychiatric disorders

April 16, 2013

Anath Lionel, a NeuroDevNet-funded PhD candidate, and a team led by NeuroDevNet investigator Dr. Steve Scherer from The Hospital for Sick Children and the University of Toronto have published a study identifying that mutations in gephyrin, a gene that plays a key role in the developing brain, are part of the genetic story behind autism, schizophrenia, and epilepsy.

“Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures” appears in the March online edition of the journal Human Molecular Genetics.

The discovery of microdeletions – very small amounts of missing DNA – in gephyrin "represents another important step in unraveling the causes of neurodevelopmental disorders,” says team leader Dr. Scherer. “Here, we used the power of genomics to find lesions in DNA that cause autism and epilepsy, which will facilitate diagnostics and therapeutic design.”

“Gephryin is a gene that was discovered about 20 years ago,” explains Lionel. “It’s a scaffolding protein, and plays a very important role in the formation of the synapse, and how brain cells communicate with each other.”

Gephyrin helps cluster GABA (4-aminobutyric acid) receptors at the synapse. GABA is the most common inhibitory neurotransmitter in the central nervous system, and acts to reduce the activity of the neurons to which it binds. Some researchers believe GABA may control the fear or anxiety experienced when neurons are overexcited.

“Mutation in this particular gene is extremely rare in the population,” adds Lionel. “Several studies have found de novo (non-inherited) changes present at a higher rate in people with neuropsychiatric disorders than in the general population. Between five to 10 percent of people diagnosed with autism or schizophrenia have de novo changes. In the general population, it’s one percent or less.”

In the gephyrin study, researchers accessed genetic data from more than 8,000 patients, and 27,000 controls. “Only six patients in total had the mutation,” says Lionel. “Three of the controls did, as well.”  Each of the six patients had a neuropsychiatric diagnosis – autism, schizophrenia, or epilepsy. Lionel and his colleagues had access to parental genetic data for five of these patients, and established the gephyrin mutation was de novo in three of them.  

“Previously, no one had reported gephryin having a role in neuropsychiatric disorders,” Lionel adds. “It works with other synaptic proteins which have been shown to have mutations in autism and schizophrenia, so it made sense to look at it.”

Gephyrin clearly plays an important role, but is not the single gene responsible for neuropsychiatric disorders, explains Lionel. “Several different genes are likely involved, none of which individually may account for more than one percent of cases.

 In all three of the disorders that presented in this study, a complex interplay of genes is always involved. “It’s likely that single gene mutations like those seen at gephyrin are just one risk factor, acting together with other genetic risk factors and wider environmental factors to influence clinical traits," says Lionel.

"Further down the road,” concludes Lionel, “this discovery of gephyrin mutations will hopefully lead to earlier diagnosis of children, allowing faster and more effective clinical intervention such as behavioral therapy as well as provide a molecular target to guide drug design.”

NeuroDevNet investigators including Dr. Evdokia Anagnostou, Dr. Eric Fombonne, Dr. Peter Szatmari, Dr. Wendy Roberts, Dr. Lonnie Zwaigenbaum, and senior author Dr. Stephen Scherer were among 32 co-authors on the study.

To access the full text electronic version of  “Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures,” click here.