CURE SYNGAP1, a nonprofit patient organization, has awarded a $130,000 grant to Dr. Helen Willsey and Dr. David Kastner at the University of California, San Francisco, to study a function of the SYNGAP1 protein that sits outside its familiar role at the synapse. Willsey's lab, working in Xenopus frog models, found that SYNGAP1 protein localizes to both primary and motile cilia - the small hair-like structures on cells - and plays a role in how those cilia form. The new funding moves that work into rodent models to ask what happens to brain anatomy and behavior when that ciliary function goes wrong.
The project will use genetically modified rats carrying two different alterations to the Syngap1 gene, tracing effects from subcellular phenotyping of cilia all the way up to behavioral characterization. The aim is to connect protein deficiency and cilia dysfunction to the range of clinical features seen in SYNGAP1-Related Disorders, which include intellectual disability, gastrointestinal problems and behavioral changes - symptoms that are difficult to explain through cortical synaptic plasticity deficits alone.
Why this matters for families affected by SRD comes down to where therapies are aimed. SYNGAP1 expression extends beyond the brain, and if the protein has jobs in non-neural tissue, treatments designed purely around synaptic function may miss part of the disorder or produce unintended effects elsewhere in the body. CURE SYNGAP1 says the work should also help sort missense variants by their functional consequences, a step toward matching individual patients to the precision medicine approach most likely to help them.
The preliminary findings underpinning the grant are described in a preprint on bioRxiv, meaning they have not yet completed peer review. The rodent experiments now funded are the test of whether the cilia connection holds up in mammals, with the researchers stating that their analysis is being conducted with rational drug design in mind.