New disease models for investigating SynGAP1-related disorder (SRD) caused by a common heterozygous nonsense SYNGAP1 mutation

The recurrent SYNGAP1 c.427C>T, p.(Arg143Ter) nonsense mutation reduces SynGAP1 protein levels and dysregulates Ras/ERK signaling in human forebrain organoids and a humanized knock-in mouse model.

• Why it matters: SynGAP1-related disorder (SRD) is severe and lifelong, and existing models may not capture mutation-specific biology needed to guide gene-therapy development.
• What they did: An integrated pipeline combined patient-derived hiPSC neuronal and forebrain organoid models with a humanized knock-in mouse carrying c.427C>T to assess molecular phenotypes and behavior.
• The result: In vivo, the c.427C>T mice show hyperactivity linked to patient-like features, supporting these models as a translational platform for evaluating SYNGAP1 single-nucleotide gene therapies.

AI summary of the abstract · may contain errors · not medical advice · read the paper.