Characterization of spontaneous seizures and EEG abnormalities in a mouse model of the human A350V IQSEC2 mutation and identification of a possible target for precision medicine based therapy.

IQSEC2 is an X-linked gene localized to the post synaptic density encoding a GTP exchange factor that regulates NMDA mediated changes in synaptic function. Mutations in the IQSEC2 gene are associated with drug resistant epilepsy, intellectual disability and autism. Precision medicine based therapeutics to treat IQSEC2 associated epilepsy requires the development and characterization of mutation specific animal models.

Housing of A350V IQSEC2 pups at 37 °C ambient temperature prevents seizures and permits the development of social vocalizations in adulthood.

Objectives: Mutations in the human IQSEC2 gene are associated with drug-resistant epilepsy and severe behavioral dysfunction. We have focused on understanding one human IQSEC2 missense mutation (A350V) for which we have created a corresponding A350V IQSEC2 mouse model by CRISPR which demonstrates seizures when the mice are 15-20 days old and impaired social vocalizations in adulthood. We observed that a child with the A350V mutation stops having seizures when experiencing a fever of greater than 38 °C.

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors.

We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2.