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Molecular Autism

, 5:16

First Online: 24 February 2014Received: 08 June 2013Accepted: 04 February 2014

Abstract

BackgroundFragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder ASD. Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity.

MethodsTo explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis.

ResultsDifferentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout Fmr1- KO model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous +-− mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues.

ConclusionsOur data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1- KO and Tsc2+-− mice mirror some, but not all, of the perturbed molecular pathways in the brain.

KeywordsFragile X syndrome Tuberous sclerosis Autism Cerebellum Blood Gene expression Murine model AbbreviationsAktv-Akt murine thymoma viral oncogene

ASDAutism spectrum disorder

CA1Cornu ammonis 1

Chd7Chromodomain-helicase-DNA-binding protein 7

DgkbDiacylglycerol kinase beta

DgkgDiacylglycerol kinase gamma

DgkhDiacylglycerol kinase eta

EGFEpidermal growth factor

EIF4EEukaryotic translation initiation factor 4E

EPS8Epidermal growth factor receptor pathway substrate 8

EPS8L1Epidermal growth factor receptor pathway substrate 8 like 1

FDRFalse discovery rate

Fmr1Fragile X mental retardation 1

FMRPFragile X mental retardation protein

FXSFragile X syndrome

Grin3aN-methyl-D-aspartate receptor subtype 3a

GSEAGene set enrichment analysis

Inpp4bInositol polyphosphate-4-phosphatase, type II

Inpp5aType I inositol-1,4,5-trisphosphate 5-phosphatase

Itpr3Inositol 1,4,5-trisphosphate receptor, type 3

KEGGKyoto encyclopedia of genes and genomes

KOKnockout

mGluRMetabotropic glutamate receptor

mTORMammalian target of rapamycin

mTORC1Mammalian target of rapamycin complex 1

OxtrOxytocin receptor

PI3KPhosphatidylinositide 3-kinases

Plcb41-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-4

PLIERProbe logarithmic Intensity error model

PrkcaProtein kinase C, alpha

PTENPhosphatase and tensin homolog

RNA-seqmRNA sequencing

Taf1cTATA box-binding protein-associated factor RNA polymerase I subunit C

TmlheTrimethyllysine dioxygenase

TSCTuberous sclerosis complex

Tsc1Tuberous sclerosis protein 1

Tsc2Tuberous sclerosis protein 2

WTWild type.

Electronic supplementary materialThe online version of this article doi:10.1186-2040-2392-5-16 contains supplementary material, which is available to authorized users.

Sek Won Kong, Mustafa Sahin contributed equally to this work.

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Author: Sek Won Kong - Mustafa Sahin - Christin D Collins - Mary H Wertz - Malcolm G Campbell - Jarrett D Leech - Dilja Kruege

Source: https://link.springer.com/







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