Cheryl Shoubridge
University of Adelaide
Title: Iqsec2 knockout mice recapitulate the intellectual disability and epilepsy phenotype of patients with loss-of-function mutations
Biography
Biography: Cheryl Shoubridge
Abstract
The IQ motif and SEC7 domain-containing protein 2 (IQSEC2) is an X-chromosome gene mutated in both males and females leading to intellectual disability (ID) and severe early-onset seizures. The pathogenesis underpinning these mutations remains unknown. Utilising CRISPR/Cas9 targeted editing (Prof PQ Thomas, SA Genome Editing Facility, University of Adelaide) we have generated an Iqsec2 KO mouse model to investigate the molecular and cellular deficits in this gene resulting in disease outcomes; a fundamental step towards the design and implementation of potential treatment options. We confirmed the loss of Iqsec2 mRNA expression and the lack of Iqsec2 protein detected within the brain of founder and progeny mice. Recapitulating the human setting, both male (48%) and female (45%) Iqsec2 KO mice present with frequent and recurrent seizures. There was an increased occurrence of seizures, reabsorption and unsuccessful nurturing of live young in breeding females. Developmentally, the KO mice exhibit significantly increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition; recapitulating the psychiatric issues, autistic-like features and cognitive deficits present in patients with loss-of-function IQSEC2 mutations. Interestingly, the loss of Iqsec2 function not only causes severe ID and seizures in KO male mice, but in agreement with the patient setting, similar severity is also noted in females despite being in a heterozygous state for this X-chromosome gene. We contend this newly generated mouse model provides a highly relevant biological tool required to interrogate IQSEC2/Iqsec2 function in the brain.