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Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action.

ABSTRACT: BACKGROUND: Austism spectrum disorder (ASD) is a heterogeneous behavioral disorder or condition characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a core clinical disability. METHODS: Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA constructs. Whole genome expression analysis was conducted for each of the knockdown cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing an anti-luciferase shRNA. Gene set enrichment and a causal reasoning engine was employed to identify pathway level perturbations generated by the transcript knockdown. RESULTS: Quantification of the shRNA targets confirmed the successful knockdown at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. CONCLUSIONS: This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients.

SUBMITTER: Lanz TA

PROVIDER: S-EPMC4176301 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action.

Lanz Thomas A TA Guilmette Edward E Gosink Mark M MM Fischer James E JE Fitzgerald Lawrence W LW Stephenson Diane T DT Pletcher Mathew T MT

Molecular autism 20131115 1

<h4>Background</h4>Austism spectrum disorder (ASD) is a heterogeneous behavioral disorder or condition characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goa ...[more]

PMID: 24238429

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Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action.

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Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action.

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