1. Autism and NrCAM Brett Maricque Image from http://newparent.com/blogs/new-parent- report/saliva-test-for-autism-in-the-works/

2. Autism Developmental disorder characterized by social impairments, communication problems, unusual/repetitive mannerisms, etc. [1,2] Group of disorders known as autism spectrum disorders (ASD) [3] CASE 1 CASE 2 CASE 1 CASE 2 1970s: ~ 1 in 2,500 children 2009: ~ 1 in 150 children Statistics from National Institute of Health, Autism Fact Sheet, 2009. Image from http://www.displaysforschools.com/autism.gif

3. Image from http://www.telegraph.co.uk/telegraph/multimedia/archive/00640/news-graphics-2007-_640547a.jpg. Data from http://ovidsp.tx.ovid.com/spa/ovidweb.cgihttp://www.telegraph.co.uk/telegraph/multimedia/archive/00640/news-graphics-2007-_640547a.jpg

4. Headlines from Washington Post (top) at washingtonpost.com and NY Times (middle, bottom) at nytimes.com. Image from http://www.babble.com/CS/blogs/famecrawler/jenny-mccarthy-jim-carrey.jpg

5. Disease-gene association Haplotype mapping Is NrCAM an appropriate target gene? Image fromhttp://www.ncbi.nlm.nih.gov/pubmed/18664314?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed. Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

6. NrCAM structure I-setIgFN3 Homo sapiens isoform A Homo sapiens isoform B Pan troglodytes Mus musculus Rattus norvegicus Caenorhabditis elegans (LAD-1) Drosophila melanogaster (neuroglian) Modified from http://pfam.sanger.ac.uk/.

7. NrCAM functionality Gene Ontology: neuron migration axon fasciculation synaptogenesis central nervous system development cell-cell adhesion ankyrin binding integral to plasma membrane Homo sapiens isoform A Gene ontology from GO Consortium at http://www.geneontology.org/. Images from http://pfam.sanger.ac.uk/structure.http://www.geneontology.org/ Ig domain I-set domain FN3 domain

8. Gene homologues D. melanogaster Neuroglian: Martin V Author, et al.Martin V Author, et al.The L1-type cell adhesion molecule Neuroglian is necessary for maintenance of sensory axon advance in the Drosophila embryo. Neural Dev 3, 10(2008). C. elegans LAD-1: Wang X Author, et al.Wang X Author, et al.The C. elegans L1CAM homologue LAD-2 functions as a coreceptor in MAB-20/Sema2 mediated axon guidance. J Cell Biol 180, 233 46(2008). Chen L. Et al. LAD-1 the Caenorhabditis elegans L1CAM homologue, participates in embryonic and gonadal morhogenesis and is a sucstrate for fibroblast growth factor receptor pathway-dependent phosphotyrosine-based J Cell Biol 154, 841 55(2001). Upregulated LAD-1 expression in nervous system during morphogenesis, localized in plasma membrane of neurons. Image from WormBase at http://www.wormbase.org/db/gene/expression?name=Expr1650

9. NrCAM localiztion 11.5 week old embryonic mouse Localization in the spinal cord Image from http://www.abcam.com/NrCAM-antibody-Neuronal-Marker-ab24344.html

10. NrCAM phylogeney ClustalW alignment [4] MUSCLE alignment [4] Phylogenetic trees taken from Phylogeney.fr at http://www.phylogeny.fr/

11. NrCAM interactions Protein network from STRING 8.0 at http://string.embl.de/newstring_cgi/show_network_section.pl. Protein information from GeneCards at http://www.genecards.org/index.shtml.http://string.embl.de/newstring_cgi/show_network_section.pl LEF1: Wnt signaling pathway, transcriptional activator ALCAM: T-cell and B-cell binding, neural cell interactions ANK2: cell motility, maintenance of specialized membrane domains ANK3: membrane- cytoskeleton linker, adhesion molecule targeting

12. Why are these relationships important? Interactions with neuronal network-associated proteins Support for functionality hypotheses Provides targets for future studies How do these proteins work together during development? Image from http://kirstyne.files.wordpress.com/2008/03/cartoon2.jpg

13. Future directions Larger GWAS: polymorphisms associated with autism Localization studies: protein interactions, tissue specificity Animal models: functionality of the protein, how do mutant proteins function KO phenotype Mutant phenotype Gene therapy: NrCAM replacement When is NrCAM functionally important? Developmentally? Clinical relevance of our current knowledge? Social implications? Images from https://secure2.convio.net/ida/site/Advocacy?cmd=display&page=UserAction&id=1231

14. Take home messages Social effects of autism need particular attention NrCAM seems to be a good target gene for autism research

15. Thank you!

16. Questions?? Image from http://www.dailymail.co.uk/news/article-553755/See-amazing-picture-autistic-artist-drew-London-memory-single-helicopter-trip.html

17. References 1.Autism Society of America. About Autism. Retrieved February 1, 2009 from ﾊ http://www.autism- society.org/site/PageServer?pagename=about_home http://www.autism- society.org/site/PageServer?pagename=about_home 2.National Institute of Neurological Disorders and Stroke. Autism Fact Sheet. Retrieved February 2, 2009 from http://www.ninds.nih.gov/disorders/autism/detail_autism.htm http://www.ninds.nih.gov/disorders/autism/detail_autism.htm 3.Fighting Autism. Autism Prevalence, Public Schools State Rankings. Retrieved February 2, 2009 from http://www.fightingautism.org/idea/autism-state-rankings.php http://www.fightingautism.org/idea/autism-state-rankings.php 4.Dereeper A., Guignon V., Blanc G., Audic S., Buffet S., Chevenet F., Dufayard J.-F., Guindon S., Lefort V., Lescot M., Claverie J.-M., Gascuel O. Phylogeny.fr: robust phylogenetic analysis for the non-specialist Nucleic Acids Research. 2008 Jul 1; 36 (Web Server Issue):W465-9. Epub 2008 Apr 19.