Data Science

Neuroscientists Solve the Puzzle of the Gene-Protein Duo Behind SYNGAP1

SynGap Mutant Neurons

Images above show normal neurons (left) and the enlarged dendritic spine of neurons with SYNGAP1 mutations.

Courtesy of Richard Huganir

Most infants fuss and cry when they get sick, but Landen showed little sign of pain. Instead, when illness struck, Landen simply slowed down a bit.

In addition to his insensitivity to discomfort, Landen gets seizures, has an autism diagnosis, and at 12 years old knows about 100 words.

When he was born in 2006, Landen’s disorder had no name — just a constellation of symptoms that Lisa and her husband managed the best they could. It took genome sequencing in 2015 to match his condition to a recently discovered syndrome. Due to a mutation in a gene called SYNGAP1 — possibly a single additional letter — Landen’s brain can’t make enough of the SYNGAP1 protein, which keeps neural wiring in check as we grow and promotes learning and memory in adults.

It’s estimated that one percent of all intellectual disability not explained by a known syndrome is caused by these mutations.

Thanks largely to the online organization of affected families, researchers now know of hundreds of children like Landen, with thousands more waiting undiagnosed. “It’s estimated that one percent of all intellectual disability not explained by a known syndrome is caused by these mutations,” says Society for Neuroscience past president, Richard Huganir, a neuroscientist at John Hopkins University and co-discoverer of the gene-protein duo. “That’s lots and lots of kids.”

As genetic sequencing becomes more affordable and the ranks of families seeking answers swell, neuroscientists like Huganir — who began their careers studying basic brain function — find themselves thrust toward the front lines of clinical research, turning neuroscience theory toward the search for treatments, and perhaps even cures.

SYNGAP1 mutations occur randomly in sperm or eggs and leave the brain with half the number of SYNGAP1 proteins it needs to develop normally. The protein stops neurons from sprouting too many connections, and without it, young brains grow wild and unruly. These extra sensitive circuits fail to extract much useful information about the world, impeding learning. Such overly connected brains are prone to epilepsy and a host of other symptoms.

Yet, exactly how specific circuits respond to the mutation remains an active area of inquiry, says Gavin Rumbaugh, a neuroscientist at Scripps Research who once worked with Huganir. Rumbaugh’s research suggests the condition mutes, not intensifies, the response of sensory circuits such as touch, possibly explaining Landen’s tendency not to outwardly show distress. He speculates the intellectual disability may stem from a distortion of information that SYNGAP1 people receive from their senses. “They may not experience the world in the same way as neurotypical children,” he says.

Huganir and Caltech neuroscientist Mary Kennedy independently discovered the SYNGAP1 gene and protein in 1998 while trying to work out how the brain develops during infancy and how it processes information in adults. About a decade later, their work leapt from lab to clinic when a genetic analysis of three individuals linked their intellectual disability with mutations in their SYNGAP1 gene. Nearly overnight, Rumbaugh decided to take his recently formed neuroscience lab in a more clinical direction. “That day I said, ‘let’s model this in mice and try to understand what happens to brain development when you lose one copy of SYNGAP1,’” he recalls.

Increased accessibility of gene sequencing gave a growing group of families a name for their child’s disorder but little else. One parent, Monica Weldon, started a Facebook group that grew into Bridge the Gap, a foundation that keeps families updated on research and maintains a patient registry to connect SYNGAP1 children with researchers. The database, where parents can log symptoms and other information, helps researchers connect dots that would otherwise be hard to see from the relatively small number of published case studies. Database reports of children like Landen not responding to pain, for instance, inspired Rumbaugh to investigate sensory circuits.

Recently Rumbaugh and Huganir have been studying complimentary approaches to improving the lives of people with SYNGAP1 mutations. Rumbaugh seeks a drug that will restore normal levels of the SYNGAP1 protein. Such a treatment could help infants with SYNGAP1 mutations develop more normal neural wiring, and recent research in mice suggests that boosting the SYNGAP1 protein could also decrease seizure rates even in more fully developed adolescents and adults, welcome news for children like Landen, who are rapidly approaching their teenage years.

Huganir’s approach, meanwhile, looks at ways to curb the activity of a protein group called RAS. SYNGAP mutations activate RAS proteins and inhibiting them could stop neurons from getting so overdeveloped. Unpublished work and two case studies suggest that statin drugs, often used to lower cholesterol, may be able to interfere with RAS activity and rescue some effects of SYNGAP1 mutation. He is also looking at ways to genetically restore normal SYNGAP protein expression.

Longer term, Huganir hopes gene editing tools will mature to the point where they can correct the genetic typo from the very beginning, sidestepping the need to fiddle with proteins in developing brains. “Those are approaches that lots of people are thinking about,” he says, “and probably will be viable in the next five to 10 years.”

  1. How were the SYNGAP1 gene and protein discovered?
  2. What questions are neuroscientists still trying to answer about SYNGAP1?
  3. What innovations are neuroscientists hoping to develop in the future for SYNGAP1 treatment?

(2019, April 30) SYNGAP1-related intellectual disability. Retrieved from

Clement, J. P., Aceti, M., Creson, T. K., Ozkan, E. D., Shi, Y., Reish, N. J., … Rumbaugh, G. (2012). Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses. Cell, 151(4), 709–723. doi: 10.1016/j.cell.2012.08.045

Cook, E. H., Masaki, J. T., Guter, S. J., & Najjar, F. (2019). Lovastatin Treatment of a Patient with a De Novo SYNGAP1 Protein Truncating Variant. Journal of Child and Adolescent Psychopharmacology, 29(4), 321–322. doi: 10.1089/cap.2018.0159

Hamdan, F. F., Gauthier, J., Spiegelman, D., Noreau, A., Yang, Y., Pellerin, S., … Michaud, J. L. (2009). Mutations in SYNGAP1 in Autosomal Nonsyndromic Mental Retardation. New England Journal of Medicine, 360(6), 599–605. doi: 10.1056/NEJMoa0805392

Michaelson, S. D., Ozkan, E. D., Aceti, M., Maity, S., Llamosas, N., Weldon, M., … Rumbaugh, G. (2018). SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. Nature Neuroscience, 21(12), 1–13.
doi: 10.1038/s41593-018-0268-0

The Deciphering Developmental Disorders Study, Fitzgerald, T. W., Gerety, S. S., Jones, W. D., van Kogelenberg, M., King, D. A., … Hurles, M. E. (2014). Large-scale discovery of novel genetic causes of developmental disorders. Nature, 519, 223–228. doi: 10.1038/nature14135

Weldon, M., Kilinc, M., Lloyd Holder, J., & Rumbaugh, G. (2018). The first international conference on SYNGAP1-related brain disorders: a stakeholder meeting of families, researchers, clinicians, and regulators. Journal of Neurodevelopmental Disorders, 10(1), 6.
doi: 10.1186/s11689-018-9225-1

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