Bioinformatic Investigation of NRXN1 Mutations Relevant to Autism Spectrum Disorder (ASD)




Associate Professor of Psychiatry

Project Summary

The Penn Undergraduate Research Mentorship (PURM) Program afforded me the opportunity to work on the Asperger Syndrome/Autism Spectrum Program of Excellence (ASPE) study in Dr. Edward Brodkin’s lab. Overall, I am very grateful that I have been able to gain exposure to the field of medical genetics and develop an array of research skills ranging from reviewing PubMed literature to mapping mutations onto protein domains.

The objective of the ASPE study is to further elucidate the genetic basis of Asperger Syndrome through genomic analyses of extended families, with a particular focus on the autism risk gene, neurexin-1 (NRXN1). Contributing to the efforts of this study, the goal of my project was to catalogue all the NRXN1 mutations with reported associations with autism through a bioinformatics approach.

The first stage of my project consisted of an extensive review of literature published on the databases, PubMed and Embase. Essentially, I optimized a series of search terms to gather all the studies with original data, identifying specific NRXN1 mutations in individuals with autism. In the second stage of my project, I worked to classify these published mutations and determine which part of the neurexin protein they affected. I learned how to use the program, Genome Browser, to determine the chromosome position, size, and exonic location of the mutations. Additionally, I utilized the programs, dbSNP and Variant Effect Predictor (VEP), to ascertain the allele change, the amino acid change and current information on the clinical significance of reported point mutations. With this information at hand, in the third stage of my project, I worked to use the chromosome positions, codon numbers, and exonic locations to map the mutations onto the domains of the protein. Furthermore, I learned how to use the program, Chimera, to generate 3D ribbon structures of the neurexin proteins, on which I could place the point mutations and highlight the affected amino acid residues.

All in all, my project established a database of NRXN1 mutations that have previously been identified in autism patients, and the hope is that it will be a useful resource to refer to and build upon as genetic data is gathered over the course of the ASPE study. With additional data from the participants of the ASPE study, I believe that we will be able to pinpoint the mutations with the most significant risk for autism, which will allow for streamlining of efforts in investigating their respective structural and functional implications.

Personally, as a pre-med student, by participating on this project through PURM, I have certainly gained greater insight on the process of translational research, as I now really understand the nature of the research that proceed clinical trials. After truly enjoying my research experience

Bioinformatic Investigation of NRXN1 Mutations Relevant to Autism Spectrum Disorder (ASD)