Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation.
Date of Issue2010
School of Biological Sciences
Angelman syndrome (AS) is a human neurological disorder caused by lack of maternal UBE3A expression in the brain. Currently, the pathogenesis of AS, and how deficiency of maternal UBE3A can upset cellular homeostasis, remains vague. In this study, we performed a genomewide microarray analysis on the Ube3a maternal deficient (Ube3am-/p+) AS mouse to search for genes affected in the absence of Ube3a. We observed 64 differentially expressed transcripts (7 up-regulated and 57 down-regulated) showing more than 1.5-fold differences in expression (p<0.05) when compared to wildtype mice. Pathway analysis shows that these genes are implicated in three major networks associated with signalin, nervous system development and cell death. Using quantitative reverse transcription PCR (qRT-PCR), we validated the differential expression of genes (Fgf7, Glra1, Mc1r, Nr4a2, Slc5a7 and Epha6) that shows functional relevance to AS phenotype. We also show that the protein level of Mc1r and Nr4a2 in the AS mice cerebellum are decreased relative to that of the wildtype mice. Consistent with this finding, expression of small interfering RNA that targets Ube3a in P19 cells caused down-regulation of Mc1r and Nr4a2, whereas overexpression of Ube3a results in the up-regulation of Mc1r and Nr4a2 when compared to mock transfected cells. These observation aid in providing insights into the genesis of neurodevelopmental phenotype of AS and highlight specific area for future research.
European journal of human genetics
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