Difference between revisions of "Genetics"

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(Genetics)
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<tr><td><b>[[ERK and P13K]]</b></td><td><b>[[Ubiquitin]]</b></td></tr><tr><td><b>[[RELN]]</b></td><td><b>[[Neurotrophins]]</b></td></tr>
 
<tr><td><b>[[ERK and P13K]]</b></td><td><b>[[Ubiquitin]]</b></td></tr><tr><td><b>[[RELN]]</b></td><td><b>[[Neurotrophins]]</b></td></tr>
 
<tr><td><b>[[CNTNAP-2]]</b></td><td><b>[[Serotoninergic, GABAergic, and glutamatergic pathways|Serotoninergic, GABAergic,<br>and glutamatergic pathways]]</b></td></tr><tr><td><b>[[EIF4E]]</b></td><td><b>[[PTEN]]</b></td></tr>
 
<tr><td><b>[[CNTNAP-2]]</b></td><td><b>[[Serotoninergic, GABAergic, and glutamatergic pathways|Serotoninergic, GABAergic,<br>and glutamatergic pathways]]</b></td></tr><tr><td><b>[[EIF4E]]</b></td><td><b>[[PTEN]]</b></td></tr>
<tr><td><b>[[Neurotrophins]]</b></td><td><b>[[Oxytocin and AVP]]</b></td></tr></table>
+
<tr><td><b>[[Neurotrophins]]</b></td><td><b>[[Oxytocin and AVP]]</b></td></tr>
 +
<tr><td><b>[[DIAPH3]]</b></td><td></td></tr></table>
  
 
<div style="text-align:center;">[[Image:Anaphase_IF.gif]]</div>
 
<div style="text-align:center;">[[Image:Anaphase_IF.gif]]</div>

Revision as of 10:15, 24 March 2010

Genetics

Want more information about a
specific gene or gene group? Pick one of the categories below!
CadherinsNeuroligins/Neurexins/Shank3
METCNVs
ERK and P13KUbiquitin
RELNNeurotrophins
CNTNAP-2Serotoninergic, GABAergic,
and glutamatergic pathways
EIF4EPTEN
NeurotrophinsOxytocin and AVP
DIAPH3
Anaphase IF.gif


A host of genes of interest have been identified through gene association studies, resequencing and, recently, the assessment of copy number variation (CNV).In particular, given the pathology of ASD, genes dealing with electrical conductance and neural transmission have been popular sites of study since synaptic dysfunction has been suggested as a unifying theme behind the various disorders in ASD. It has been difficult to find a specific gene mutation that is present in all cases of ASD, probably because of the heterogeneity of the ASD population. However, one group found that when they stratified an ASD group into subgroups based off of severity of symptoms and applied cluster analysis and various genetic profiling techniques, there were 20 novel genes that were shared by all three ASD subgroups. Additionally, most of the highly significantly differentially expressed genes in the ASD group that was found in the study are differentially regulated within the context of androgen insensitivity. This supports one hypothesis that higher levels of fetal testosterone are a risk factor for ASD.1

The high occurrence of differential expression profiles for 15 clock genes only for those in the severely affected ASD subgroup suggest that the severity of symptoms may be a connected with the dysregulation of the circadian rhythm. Scientists have demonstrated a genetic association of PER1 and NPAS2 with autistic disorder, and other theories have been proposed interplays between Fragile-X related proteins and synaptic genes with circadian rhythm genes.1

Most approaches to finding loci of interest are under one of two assumptions:

  1. ASD is a result of interplay between many genes
  2. There is one principle gene which contributes to many aspects of the disease.

The idea that the symptoms of ASD is a result of the interaction of many different genes has been supported by linkage studies, and the fact that although many genes have been identified with causing ASD symptoms, each of these individual genes do not cause more than 1-2% of all ASD cases. However, data mining techniques such as hierarchical clustering and principle components analysis find that it is highly likely that there is 1 continuously distributed factor contributing to many aspects of ASD, thereby validating the existence of the second hypothesis. Additionally, statistical analysis of ASD family data suggest a large portion of ASDs may be the result of dominant de novo mutations that have reduced penetrance in families.

Methylation-One other hypothesis that may account for the widespread genetic defects found in ASD patients is that there may be abnormal methylation of brain-expressed genes on the X chromosome which in turn causes abnormal expression levels of genes important during development. These alternations cause one or more genes on the single X chromosome in males to be either partially silenced or over-expressed. This similarly happens in females, but the random X-chromosome inactivation might lesson autism predisposition and prevalence in females. This proposal is consistent with the findings that males make up a significantly larger amounts of ASD cases than females.2

Linkage and Association Studies

Successful linkage studies in the past have been mostly based on affected sibling-pair designs in multiplex families. However, there were no genome wide significant results probably because of small effect sizes that were a result of any single gene. Even large scale studies showed only minor overlap, likely because of variety of phenotypes in ASD. Recently though, use of endophenotypes and QTL mapping have increased the power of linkage and association studies.

Endophenotypes can help genetic studies by defining more etiologically homogenous subgroups. Furthermore, endophenotypes are measurable in both affected and control groups, thus allowing for larger sample sizes. Language phenotypes such as the age at which the child speaks their first word, are very promising endophenotypes because they show significant linkage in many samples and the support has been lent at implicating the 7q region to this language development, thereby raising hypothesis that the 7q region is home to other loci that are associated with the autism language phenotype3.

Copy-Number Variation CNVs in certain dosage sensitive genes have been suggested as the root cause of ASD. This theory is particularly appealing because CNVs have a high locus-specific rate of new nucleotide mutations, 3-4 times the rate for single nucleotide polymorphisms. Additionally, CNVs can account for the phenotypic variation seen in ASD. The type of copy number rearrangement and whether it was inherited maternally or paternally can further affect the phenotype. For example, duplications of chromosome 15q11-q13 that are derived maternally confers a high risk of ASD (>85%) while those inherited paternally have anywhere from no phenotypic affects to mild developmental and cognitive impairment. There is relative enrichment within CNVs for neuronal synaptic complex genes, particularly SHANK3, NLGN4, and NRXN1. However, it is difficult to know right now how harmful a particular inherited CNV will be because the extent of the CNV and what genes are included, as well as which geens are nearby can influence the phenotypes. Specifically, other genes can modulate the risk of genes that normally confer genes, and other genes can even act protectively to decrease the risk of developing a particular genetic disease4.

Some likely candidate genes that have been explored include

GeneFunctionLocationsource
UBE3Atranscribed protein is an enzyme that works in protein degradation15q11-q13PMID 18414403
GABRB3encodes a member of of a ligand gated ionic channels responsible for inhibition in nervous system15q11-q12PMID 18414403
METencodes receptor tyrosine kinase involved in neuroal growth and organization, immunological and gastrointestinal functioning7q31 PMID 18716561
SLC6A4serotonin transporter17q11PMID 18716561
RELNencodes protein that controls intercellular interactions involved in neuronal migration and positioning in brain development7q22PMID 18716561
CNTNAP2part of neurexin superfamily, encodes CASPR2, a transmembrane scaffolding protein 7q35-q36PMID 18179894


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Analytical Techniques

Citations

1. Schmitz C. Autism: neuropathology, alterations of the GABAergic system, and animal models.Int Rev Neurobiol. 2005;71:1-26. PMID 16512344

2. Jones, J.R. et. al. Hypothesis: Dysregulation of Methylation of Brain-Expressed Genes on the X Chromosome and Autism Spectrum Disorders. American Journal of Medical Genetics Part A 146A:2213-2220 (2008). PMID 18698615

3. Lush, Molly et. al. Current Developments in the Genetics of Autism: From Phenome to Genome. J Neuropathol Exp Neurol. 2008 September; 67(9):829-837. PMID 18716561

4. Cook, E.H. and S. W. Scherer. Copy-number variations associated wtih neuropsychiatric conditions. Nature.2008 October;455(16) 919-23. PMID 18923514