Autism and NrCAM Brett Maricque Image from report/saliva-test-for-autism-in-the-works/

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 s: ~ 1 in 2,500 children 2009: ~ 1 in 150 children Statistics from National Institute of Health, Autism Fact Sheet, Image from

Image from Data from

Headlines from Washington Post (top) at washingtonpost.com and NY Times (middle, bottom) at nytimes.com. Image from

Disease-gene association Haplotype mapping Is NrCAM an appropriate target gene? Image fromhttp:// Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

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

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 Images from Ig domain I-set domain FN3 domain

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, (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, (2001). Upregulated LAD-1 expression in nervous system during morphogenesis, localized in plasma membrane of neurons. Image from WormBase at

NrCAM localiztion 11.5 week old embryonic mouse Localization in the spinal cord Image from

NrCAM phylogeney ClustalW alignment [4] MUSCLE alignment [4] Phylogenetic trees taken from Phylogeney.fr at

NrCAM interactions Protein network from STRING 8.0 at Protein information from GeneCards at 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

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

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

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

Thank you!

Questions?? Image from

References 1.Autism Society of America. About Autism. Retrieved February 1, 2009 from ﾊ society.org/site/PageServer?pagename=about_home society.org/site/PageServer?pagename=about_home 2.National Institute of Neurological Disorders and Stroke. Autism Fact Sheet. Retrieved February 2, 2009 from Fighting Autism. Autism Prevalence, Public Schools State Rankings. Retrieved February 2, 2009 from 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 Jul 1; 36 (Web Server Issue):W Epub 2008 Apr 19.