Neuroligins/Neurexins/Shank3

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Neurexins

  • History

Neuroexins were initially discovered as the binding receptor for the vertebrate-specific toxin alpha-latrotoxin, a large protein that binds to presynaptic receptors and induces massive neurotransmitter release.


  • What are they?

There are two different types of neurexins: alpha-nrxn and beta-nrxn. They differ in the N-terminal extracellular sequence. Neurons also express the neurexin related proteins CASPRs which resemble alpha-neurexin in structure, but contain additional extracellular domains. CASPRs are mostly involved in neuron-glia interactions outside of synapses. Neurexins can be spliced in 5 different positions to create thousands of neurexin isoforms. Different alpha and beta neurexins are expressed in the same neuron classes, but each type of neurexin is differentially distributed among different classes of neurons. Alpha-neurexin is located on presynaptic terminals and partly present on postsynaptic sites.

Neurexins are necessary for the proper functioning of Ca2+ channels and neurotransmitter release.8

Neuroligins

  • History

Neuroligins were first identified when it was found that they bind to beta-neurexins.8

  • What are they?

Neuroligins are type-1 membraine proteins with a simpler domain structure. They are adhesion molecules that have extracellular domains to participate in trans-synaptic adhesion and cytoplasmic domains which can interact with intracellular proteins.7 Mammals express 4 neuroligind genes, where neuroligins 3 and 4 are localized on the X-chromosome. In addition, humans have neuroligin 5 on the Y chromosome, which complements neuroligin 4.


Nlgn3 and Nlgn4

The neuroligins are an attractive target to investigate for ASD research because they are thought to be vital in the formation of neural circuits. Given the higher prevalence of autism in males, nlgn3 and nlgn4 have received extra attention because they are located on the X-chromosome. Results from studies, however, have been conflicting. Some have detected genetic variants in NLGN3 and NLGN4 in probands with autism, mental retardation, or pervasive developmental disorders 1, 2. In contrast, many other attempts to find the same or new variants in different ASD patients failed.3, 4, 5, 6 Confounding factors in doing genetic association studies about ASD are the heterogeneity of the populations and the need for large sample sizes to achieve statistical significance. As it is, while many new variants that can likely cause ASD have been detected in ASD patients, these variants are probably only responsible for a small number of cases.



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SHANK3

References

1. Laumonnier F, et. al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.Am J Hum Genet. 2004 Mar;74(3):552-7PMID 14963808

2. Yan, J. et. al. Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry. 2005 Apr;10(4):329-32. PMID 15622415

3. Wermter, AK et. al. No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level. Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):535-7. PMID 18189281

4. Vincent, JB et. al. Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):82-4. PMID 15274046

5. Blasi, F. et. al. Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am J Med Genet B Neuropsychiatr Genet. 2006 Apr 5;141B(3):220-1. PMID 16508939

6. Ylisaukko-oja, T et. al. Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet. 2005 Dec;13(12):1285-92. PMID 16077734

7. Han K et. al. Synaptic adhesion molecules and PSD-95.Prog Neurobiol. 2008 Mar;84(3):263-83. PMID 18206289

8. Akins MR et. al. Cell–cell interactions in synaptogenesis.Curr Opin Neurobiol. 2006 Feb;16(1):83-9 PMID 16427268