Autism and NrCAM

Brett Maricque

Image from http://newparent.com/blogs/new-parent-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

1970s: ~ 1 in 2,500 children2009: ~ 1 in 150 children

Statistics from National Institute of Health, Autism Fact Sheet, 2009. Image from http://www.displaysforschools.com/autism.gif

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.cgi

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

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

NrCAM structure I-set Ig FN3

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/.

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.

Ig domain

I-set domain

FN3 domain

Gene homologuesD. melanogaster Neuroglian:Martin V Author , et al.The L1-type cell adhesion molecule Neuroglian is necessaryfor maintenance of sensory axon advance in the Drosophila embryo. Neural Dev 3, 10(2008).

C. elegans LAD-1:Wang X Author , et al.The C. elegans L1CAM homologue LAD-2 functions as acoreceptor 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 inembryonic and gonadal morhogenesis and is a sucstrate for fibroblast growth factorreceptor 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

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

NrCAM phylogeneyClustalW alignment [4]

MUSCLE alignment

[4]

Phylogenetic trees taken from Phylogeney.fr at http://www.phylogeny.fr/

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.

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 neuronalnetwork-associated proteins

Support for functionalityhypotheses

Provides targets for futurestudies

How do these proteins worktogether during development?

Image from http://kirstyne.files.wordpress.com/2008/03/cartoon2.jpg

Future directionsLarger GWAS: polymorphisms associated with autismLocalization studies: protein interactions, tissue specificityAnimal models: functionality of the protein, how do mutant

proteins functionKO phenotype Mutant phenotype

Gene therapy: NrCAM replacement

When is NrCAM functionally important?Developmentally? Clinical relevance of our currentknowledge? Social implications?

Images from https://secure2.convio.net/ida/site/Advocacy?cmd=display&page=UserAction&id=1231

Take home messages

Social effects of autism needparticular attention

NrCAM seems to be a good targetgene for autism research

Thank you!

Questions??

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

References

1. Autism Society of America. About Autism. Retrieved February 1, 2009 from ﾊ 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 fromhttp://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

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.