Aim of the project

Mutations in a specific gene, Neurexin 1 (NRXN1), have been implicated in the pathophysiology of autism and other neuropsychiatric conditions. Bringing together researchers from the Autism Research Centre, the Laboratory of Regenerative Medicine at Cambridge University and the Department of Basic and Clinical Neuroscience at Kings College London this project will look to fill the gaps in our knowledge about the role of this gene in autism using induced pluripotent stem cell (iPSC) technology.
The gene is located at 2p16.3 (chromosome 2), and is best known to interact with postsynaptic neuroligins (NLGNs) in order to connect two neurons at the synapse, so enabling synaptic transmission. However, NRXN1 is also known to interact with other proteins, including neurexophilins, dystroglycan, LRRTM proteins, and cerebellin.  
NRXN1 lies in a ‘vulnerable’ chromosomal region that is prone to genomic deletion. The deletion affects up to 1 in 2,500 individuals with developmental delay who typically require special learning support. Seizures, speech and language delay, motor delay, and autism have all been associated with chromosome 2p16.3 deletion. However, individuals exist with a deletion in NRXN1 who display no atypical behaviour or symptoms, posing a scientific puzzle and suggesting that other factors (other genes, epigenetic factors, hormones, etc.,) act together with mutations in NRXN1 to determine the phenotype. It is also been hypothesized that mutations in NRXN1 might be responsible for bringing about subtle changes in distinct brain regions, and not the entire brain, so introducing changes in the neuronal circuitry associated with distinct cognitive impairments in autism or schizophrenia.
Two different iPSC methodologies will be used to study NRXN1 in more detail.  The first will allow the investigation of the role of NRXN1 during early stages of human development.  The second allows for the generation of more mature cells and research to be done on these.
This project forms part of a larger research consortium involving investigators at the Asperger Syndrome Program at the University of Pennsylvania.

Importance of research

The cause of autism is complex and may result from an interplay between genetic, epigenetic (factors controlling gene expression), hormonal, and environmental factors. All these are likely to contribute to the development of autism in a subset of individuals that harbour a NRXN1 mutation, and explain why other individuals with mutations in NRXN1 may not be autistic but may have another condition, or have no symptoms at all.

Scientists involved

  • Dr Dwaipayan Adhya
  • Aicha Massrali
  • Arko Paul

Key findings

The project will run for 2 years from Q1 2018.