Key roles of C2/GAP domains in SYNGAP1-related pathophysiology

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency. However, some affected individuals carry missense mutations in its calcium/lipid binding (C2) and GAP domains, suggesting that many clinical features result from loss of functions carried out by these domains. To test this hypothesis, we targeted the exons encoding the C2 and GAP domains of SYNGAP. Rats heterozygous for this deletion exhibit reduced exploration and fear extinction, altered social investigation, and spontaneous seizures—key phenotypes shared with Syngap heterozygous null rats. Together, these findings indicate that the reduction of SYNGAP C2/GAP domain function is a main feature of SYNGAP haploinsufficiency. This rat model provides an important system for the study of ID, autism, and epilepsy. [Display omitted] •Generated rat model with heterozygous deletion of SYNGAP C2/GAP domains (Syngap+/Δ-GAP)•Homozygous lethality indicates C2/GAP domains are essential for survival•Syngap+/Δ-GAP rats exhibit seizures, reduced exploration, and impaired fear extinction•These key phenotypes are shared between Syngap+/Δ-GAP and Syngap heterozygous null mutant rats Katsanevaki et al. use a combination of molecular, cellular, circuit, and behavioral approaches to demonstrate phenotypic similarities between two distinct Syngap rat models. These findings highlight the importance of C2/GAP protein domains in the pathophysiology associated with SYNGAP1-related intellectual disability.