Investigating how mutations in IQSEC2 cause intellectual disability and severe early onset seizures in children using a mouse modelling the knockout of Iqsec2.

Chief Investigator:

Associate Professor Cheryl Shoubridge

Funding Amount:



The University of Adelaide


Intellectual disability (ID) is frequent in the population with as many as 1 in every 50 people affected. The cost to Australia of ID is estimated at $14 billion annually. Children that have mutations in the IQSEC2 gene have substantial limitations in intellectual functioning and present with autistic traits and early onset seizures. We have generated a novel mouse model with complete knockout of Iqsec2. Our study will harness this powerful resource to investigate the role of this intellectual disability gene on the development and function of the brain at the cellular and molecular level.

Research outcomes:


Cheryl Shoubridge, Matilda Jackson

Research Completed:


Research Findings:

The research of the Intellectual Disability Research laboratory at the University of Adelaide addresses the functional impact of mutations in genes that contribute to intellectual disability and epilepsy in children. Our overall aim is to understand the cellular processes required for normal development of the brain and in particular, the processes of memory and learning.  In the current study we have generated a mouse modelling the complete knockout of a gene responsible for intellectual disability and epilepsy in children using a very powerful technique called CRISPR/Cas9 gene editing.  We have established that the mutant mice present with seizures and other developmental difficulties, mirroring what we see in our human patients with similar gene mutations.  Although the full evaluation of these mice remains to be completed, we have made significant discoveries already using cells from the brains of these animals cultured in a dish in the laboratory.  Using these neurons from the brains of normal and mutant mice we have been able to establish that aspects of how these neurons grow and connect with each other is disturbed due to the mutation. The correct developments of these connections in the brain are critical for learning and memory. Our ongoing work with these mice will investigate how the complex structures of the brain are orchestrated to ensure that cognition is achieved.

Key Outcomes:

  • The ability of cells of the brain, called neurons, to connect with each other, both within the local environment and across distant regions of the brain is critical to brain function required for cognition, learning and memory. The connectivity of neurons is vast. Individual neurons communicate using a structure called the synapse. The synapse is the point at which one neuron connects and communicates with another neuron. The ability of these structures to respond and adapt during development is called ‘synaptic or brain plasticity’. Intellectual disability and seizures can arise when the development of synapses is altered or if the capacity of the plasticity of synapses is reduced.
  • Our laboratory first identified IQSEC2 as a novel gene causing intellectual disability. Following this first report in 2010, subsequent mutations reported in this gene have shown that disturbing this genes function leads to a substantial limitation in intellectual functioning, autism and early onset seizures in children.We predict that this gene is important in the correct development of neurons, in particular the development of the synapse.  As the brain is so complex, experiments in the laboratory do not always allow us to address these types of questions easily. There are currently no animals modelling the impact of IQSEC2 on the behavioural and cognitive deficits due to a complete or partial loss of this gene. Hence, we have used a powerful genome-editing tool (CRSPR/Cas9) to generate a novel mouse with the function of the IQSEC2 gene knocked out to model the mutations in our patients. Our aim was to use the knock-out mouse model to investigate the impact of IQSEC2 on the development and function of the brain, in particular the development and plasticity of neuronal synapses.

Our objectives were:

To investigate the neurological and behavioural outcomes in an Iqsec2 knock-out mouse model to better understand the role of this important disease causing gene in the correct development and functional adaptation of the brain.

  1. 1) Investigate the cellular and molecular pathology due to complete loss of endogenous Iqsec2 in the developing brain.
  2. 2) Investigate the behavioural and cognitive outcomes of Iqsec2 knockout and carrier mice compared to their wild-type littermates.

Research outcomes:

  1. 1) We were able to successfully grow neurons from the mice modelling knock-out of Iqsec2 compared to their “normal” littermates in a cell culture dish. Using this technique we have established that the correct development of the neurons and in particular the structures that contribute to the development of the synapse are delayed and are disturbed due to the knock-out of IQSEC2. We have begun to investigate the extent of this disturbed development.
  2. 2) IQSEC2 is on the X chromosome. Males only have one X-chromosome (inherited from their mother), and if this carries a gene with a mutation then the boy will be affected with the disorder. Hence, in our breeding we only get ¼ of each litter as mutant male mice and another ¼ as carrier female mice. This inheritance pattern means that breeding the required number of animals to undertake behavioral studies is not trivial. However, whilst building up the numbers of animals to undertake these studies we have established;

– optimized the breeding strategy to successfully breed using carrier mutant females despite having seizures;

–  age of onset /  frequency and  / type of seizures seen in both male and female knock-out mice;

– collected key tissues and biological samples from these animals across key stages of development to better investigate how development of the brain and individual neurons are being affected by the Knockout of IQSEC2.

Significance of the research findings – future directions:

Our findings to date indicate that the knock-out of IQSEC2 in our mouse model recapitulates the key clinical presentations in human patients with similar types of mutations in the IQEC2 gene. This means we have developed a powerful tool that we can use to interrogate just how individual neurons through to brain development is impacted and which processes contribute to intellectual disability and seizures. Our future work will use neurons from these mice in culture to tease apart the processes each neurons uses to communicate and respond as part of learning and memory. We can combine these cellular insights with our whole animal approach to begin to understand how deficits to the structures of the developing brain potentially relate to the behavioural, learning and cognitive deficits seen in our patients. This is the first step in identifying areas for potential therapeutic intervention for these devastating diseases in children.

Research Papers:

Hinze SJ, Jackson MR, Lie S, Jolly L, Field M, Barry SC, Harvey RJ and Shoubridge C. Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis–Under re-review with Translational Psych Jan 2017.

  • Conference presentations arising from this research project.

Australian Society of Neuroscience 4th– 8th Dec Hobart, Australia, 2016 (Oral Presentation)

Functional deficit of iqsec2 with missense mutations disrupts normal dendritic spine morphogenesis

Hinze SJ, Jackson MR, Lie S, Jolly L, and Shoubridge C.

International Congress of Human Genetics, Kyoto, Japan, April 3rd to 7th 2016 (Poster Presentation)

Investigating functional deficits of the intellectual disability gene, IQSEC2 on dendritic spine morphogenesis

Hinze SJ, Lie S, Jolly L, and Shoubridge C

  • Lorne Genome 12-14th Feb 2017, Victoria Australia. (Poster presentation)

IQSEC2; when two Xs are not better than one. Jackson M and Shoubridge C.   

The paper currently under review with Translational Psych Jan 2017 will be forwarded to Channel 7 as soon as accepted for publication and again once published and available on Pubmed.

Related Publications:

Future Outcomes:


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