Grant fuels research into SYNGAP1-linked behavioral abnormalities

CURE SYNGAP1 501(c)(3) is pleased to announce a $130,000 grant to Dr. Helen Willsey and Dr. David Kastner at the University of California, San Francisco (UCSF). This funding extends Dr. Willsey's identification of SYNGAP1's role in cilia formation to investigate how its disruption impacts brain anatomy and behavior, potentially leading to more precise therapies for patients with SYNGAP1-Related Disorders (SRD).

Building on previous discoveries that SYNGAP1 protein localizes to both primary and motile cilia, the research will use rodent models to investigate the link between SYNGAP1 protein deficiency, cilia dysfunction, and the diverse clinical symptoms seen in SRD patients, including intellectual disability, gastrointestinal issues, and behavioral changes. The work spans analysis from subcellular ciliary phenotyping to behavioral characterization in genetically modified rats with two different alterations to the Syngap1 gene. Investigation and analysis will be done with an eye towards informing rational drug design.

CURE SYNGAP1 is committed to improving the lives of all SRD patients. SYNGAP1-Related Disorders include many symptoms that may not solely result from cortical synaptic plasticity deficits. Moreover, it is increasingly clear that SYNGAP1 expression extends beyond the brain. Findings outlined in Dr. Willsey's preprint on bioRxiv underscore the importance of addressing the multifaceted impact of SYNGAP1 mutations. This preliminary data offers a compelling path forward, providing deeper insights into the diverse roles that SYNGAP1 protein plays in the body. Her work has the potential to broaden the range of tissues targeted by therapies, addressing many unmet medical needs affecting our patients. By uncovering previously overlooked functions of the SYNGAP1 protein, this project will also help us mitigate unintended consequences of future therapies. Additionally, her research will aid in categorizing missense variants by their functional characteristics, which is crucial for identifying the most effective precision medicine strategies for each variant.

Dr. Helen Willsey's lab at UCSF has made significant advances in understanding SYNGAP1 protein functions beyond the synapse. Her research, using Xenopus models, uncovered SYNGAP1 protein's critical role in ciliogenesis, providing crucial insights into how SYNGAP1 mutations affect both neural and non-neural tissues. These groundbreaking findings form the foundation for her current work, which now extends into rodent models, aimed at investigating how SYNGAP1 mutations impact brain structure and broader systemic functions.