The K138X mutation is predicted to result in a truncated SYNGAP1 protein that lacks the RASGAP domain (which activates ras GTPases) in addition to other functional domains (Fig. 1).11,17 The R579X and c.2438delT mutations are predicted to truncate SYNGAP1 in the middle and just after the RASGAP domain, respectively. These three mutations occur upstream of the 3′ terminus of the gene (encoding the C-terminal part of the protein) that can be alternatively spliced. This splicing process produces one of at least three possible isoforms, which differentially bind to other components of the NMDA-receptor complex, such as PSD95 and DLG3 (through the PDZ-binding motif, QTRV, in isoform 2) or CamKII (through GAAPGPPRHG in isoform 3).11,18 The importance of the QTRV motif is highlighted by the observation that its deletion impairs the ability of SYNGAP1 to regulate dendritic-spine formation.19
