Divergent dysregulation of gene expression in murine models of fragile X syndrome and tuberous sclerosis

作者：Kong Sek Won; Sahin Mustafa; Collins Christin D; Wertz Mary H; Campbell Malcolm G; Leech Jarrett D; Krueger Dilja; Bear Mark F; Kunkel Louis M; Kohane Isaac S^*

来源：Molecular Autism, 2014, 5(1): 16.

DOI：10.1186/2040-2392-5-16

• Fragile X syndrome
• Tuberous sclerosis
• Autism
• Cerebellum
• Blood
• Gene expression
• Murine model

Background: Fragile 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.
Methods: To 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.
Results: Differentially 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.
Conclusions: Our 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.

• 出版日期2014-2-24