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Using Drosophila to Discover the Biological Significance of Rare Variants Linked to ASDs

Thursday, 2 May 2013: 09:00-13:00
Banquet Hall (Kursaal Centre)
S. Mehta1, K. Pappu2, P. K. Patel2 and L. Zipursky2, (1)Semel Institute/UCLA, Los Angeles, CA, (2)Biological Chemistry, HHMI/UCLA, Los Angeles, CA
Background: The number of ASD candidate genes has increased greatly in recent years with the completion of high resolution CNV analyses on simplex and multiplex families. That number is likely to increase further as genome sequencing efforts on patients with ASDs reach completion. However, there has been a lag between the identification of these candidate genes and our understanding of the pathophysiology of ASDs that is due to our ignorance of the biological functions of many of these genes. Although simplex cases of ASDs have been shown to have a higher burden of rare variant CNVs, identifying which variants are causal in ASDs cannot be done computationally. For a few candidate genes, the use of animal models has been informative, but it is impractical to make mouse models of all of the ASD rare variants. The fruit fly, Drosophila melanogaster, is a well characterized genetic model organism that has previously been used to gain insight about human diseases, particularly neurodegenerative disorders and cancer. The low cost, short generation time, and ease of genetic manipulation make Drosophilaan ideal system for examining the biological functions of many ASD candidate genes as well as assessing the biological impact of human disease variants.

Objectives: We aim to show that Drosophila can be used to effectively study the functions of ASD candidate genes from the standpoint of neural development rather than behavior. To accomplish this, we have chosen to study Neurexin IV (the Drosophilahomolog of a highly penetrant ASD candidate gene, CNTNAP2) as a proof of principle. We will assess the impact of four evolutionarily conserved rare variants (missense mutations) in Neurexin IV that are linked to cases of Autism.

Methods: We have generated a molecularly defined loss of function allele of Neurexin IV that can allow us to selectively remove Neurexin IV in select populations of neurons. We have also generated transgenic flies that have ASD related variants of Neurexin IV and will assess their function in a Neurexin IV mutant background.

Results: Each of the missense mutations fails to rescue lethality associated with loss of endogenous Neurexin IV despite being made at physiological levels. Several of the mutations result in mislocalization of Neurexin IV, suggesting that these mutations prevent Neurexin IV from binding to its correct partners.

Conclusions: The missense mutations in Neurexin IV associated with ASD significantly impair Neurexin IV function. Given that loss of CNTNAP2 is associated with a familial form of ASD, our work provides evidence that the rare variants associated with CNTNAP2 play a causal role in the development of ASDs. We estimate that about 60% of current ASD candidate genes have a high degree of evolutionary conservation between humans and Drosophila. Based on our experiences studying Neurexin IV, Drosophila can be used to effectively probe the biological function of many ASD candidate genes and thereby increase our understanding of ASD pathophysiology.

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