Neurexins and Autism

Neurexins had come up in my Cell Neuroscience course this semester. Connection to Autism. But of course!!

Neurexins are a family of proteins that play important roles in synaptic function. They are involved in the formation, maintenance, and plasticity of synapses, which are the junctions between neurons that allow them to communicate with each other. Mutations in neurexin genes have been linked to a number of neurodevelopmental disabilities, including autism.

A few reasons why neurexin genes might be associated with autism.

• disrupt in function of synapses (& communication between neurons), which could contribute to the autistic social and communication challenges
• disruption in brain development as neurexin genes expressed early in brain development, and play important roles in the formation of neural circuits.
• impact on function of other genes as they interact with a number of other proteins.

More research is needed to understand the exact mechanisms by which mutations in neurexin genes mutations contribute to autism.

Examples of studies reporting that mutations in neurexins are associated with autism
1. Südhof, T. C. (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature, 455(7215), 903-911. doi: 10.1038/nature07456

• discusses the role of neuroligins and neurexins in synaptic function and their links to cognitive disorders, including autism. The author summarizes several studies that have identified mutations in neurexins that are associated with autism.

2. Kim, H. G., Kishikawa, S., Higgins, A. W., Seong, I. S., Donovan, D. J., Shen, Y., . . . Gusella, J. F. (2008). Disruption of neurexin 1 associated with autism spectrum disorder. American Journal of Human Genetics, 82(1), 199-207. doi: 10.1016/j.ajhg.2007.09.011

• This study reports a de novo deletion of neurexin 1 in one autistic and found that the deletion disrupted the neurexin 1 gene. They also analyzed several other autistics and identified additional mutations in neurexin 1, providing further evidence for the involvement of this gene in autism.

3. Vaags, A. K., Lionel, A. C., Sato, D., Goodenberger, M., Stein, Q. P., Curran, S., . . . Scherer, S. W. (2012). Rare deletions at the neurexin 3 locus in autism spectrum disorder. American Journal of Human Genetics, 90(1), 133-141. doi: 10.1016/j.ajhg.2011.11.025

• The authors performed genetic analyses on a cohort of autistics and identified several rare deletions that disrupted the neurexin 3 gene. They also performed functional studies on the deleted genes and found that they altered synaptic function.

4. Ching, M. S., Shen, Y., Tan, W. H., Jeste, S. S., Morrow, E. M., Chen, X., . . . Wu, B. L. (2010). Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 153(4), 937-947. doi: 10.1002/ajmg.b.31063

• This study reports that deletions of the neurexin-1 gene (NRXN1) are associated with a wide range of developmental disabilities, including autism. The authors analyzed a large cohort of people with developmental disabilities and identified several rare deletions in NRXN1. They also performed functional studies on the deleted genes and found that they altered synaptic function.

5. Rouleau, G. A. (2011). Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Human Genetics, 130(4), 563-573. doi: 10.1007/s00439-011-0975-z

• This study reports truncating mutations in both NRXN2 and NRXN1 in autism and schizophrenia. The authors performed genetic analyses on a large cohort of patients and identified several rare mutations in both genes. They also performed functional studies on the mutated genes and found that they disrupted synaptic function.