Human Molecular Genetics Advance Access originally published online on January 30, 2006
Human Molecular Genetics 2006 15(6):853-869; doi:10.1093/hmg/ddl004
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Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin–proteasome pathway processes
1Department of Pathology and 2Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA, 3Department of Human Genetics, University of California–Los Angeles, Los Angeles, CA, USA and 4Center for Pediatric Research, Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE, USA
* To whom correspondence should be addressed at: MIND Institute Wet Lab, 2805 50th St., No. 2420, Sacramento, CA 95817, USA. Tel: +1 9167030362; Fax: +1 9167030367; Email: jpgregg{at}ucdavis.edu
Received November 21, 2005; Accepted January 25, 2006
Autism is a complex neurodevelopmental disorder having both genetic and epigenetic etiological elements. Isodicentric chromosome 15 (Idic15), characterized by duplications of the multi-disorder critical region of 15q11–q14, is a relatively common cytogenetic event. When the duplication involves maternally derived content, this abnormality is strongly correlated with autism disorder. However, the mechanistic links between Idic15 and autism are ill-defined. To gain insight into the potential role of these duplications, we performed a comprehensive, genomics-based characterization of an in vitro model system consisting of lymphoblast cell lines derived from individuals with both autism and Idic15. Array-based comparative genomic hybridization using commercial single nucleotide polymorphism arrays was conducted and found to be capable of sub-classifying Idic15 samples by virtue of the lengths of the duplicated chromosomal region. In further analysis, whole-genome expression profiling revealed that 112 transcripts were significantly dysregulated in samples harboring duplications. Paramount among changing genes was ubiquitin protein ligase E3A (UBE3A; 15q11–q13), which was found to be nearly 1.5–2.0-fold up-regulated in duplicated samples at both the RNA and protein levels. Other key findings from gene expression analysis included two down-regulated genes, APP and SUMO1, with well-characterized roles in the process of apoptosis. We further demonstrate in this lymphoblast model that the gene-dosage directed increases in UBE3A levels can lead to dysregulation of the process of ubiquitination in response to genotoxic insult. This study provides insight into the direct and indirect effects of copy number gains in chromosome 15 and provides a framework for the study of these effects in neuronal systems.
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