Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes. BMC Genomics 7:118

The George Washington University Medical Center, Dept. of Biochemistry and Molecular Biology, 2300 Eye St, N.W. Washington, DC 20037, USA.
BMC Genomics (Impact Factor: 3.99). 02/2006; 7(1):118. DOI: 10.1186/1471-2164-7-118
Source: PubMed


The autism spectrum encompasses a set of complex multigenic developmental disorders that severely impact the development of language, non-verbal communication, and social skills, and are associated with odd, stereotyped, repetitive behavior and restricted interests. To date, diagnosis of these neurologically based disorders relies predominantly upon behavioral observations often prompted by delayed speech or aberrant behavior, and there are no known genes that can serve as definitive biomarkers for the disorders.
Here we demonstrate, for the first time, that lymphoblastoid cell lines from monozygotic twins discordant with respect to severity of autism and/or language impairment exhibit differential gene expression patterns on DNA microarrays. Furthermore, we show that genes important to the development, structure, and/or function of the nervous system are among the most differentially expressed genes, and that many of these genes map closely in silico to chromosomal regions containing previously reported autism candidate genes or quantitative trait loci.
Our results provide evidence that novel candidate genes for autism may be differentially expressed in lymphoid cell lines from individuals with autism spectrum disorders. This finding further suggests the possibility of developing a molecular screen for autism based on expressed biomarkers in peripheral blood lymphocytes, an easily accessible tissue. In addition, gene networks are identified that may play a role in the pathophysiology of autism.

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Available from: John Quackenbush, Apr 08, 2014
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    • "При други проучвания (Garbett, 2008, Gregg, 2008, Hu, 2006, Hu, 2009b, Enstrom, 2009) е установена диференциална експресия на гени, включени в имунната система: провъзпалителни цитокини, NK и CD8+ клетки, свързаните гени, включително рецепторни гени и гени, участващи в пътищата на цитотоксичност като ASS, DAPK1, FLT1, IL6ST (Hu, 2006), "
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    ABSTRACT: Abstract: Autism spectrum disorders (ASD) are disorders of the central nervous system characterized by impairments in communication and social reciprocity. Despite thousands of studies on this topic, the etiopathogenesis of these disorders remains unclear, apart from a general belief that they derive from an interaction between several genes and the environment. The aim of this review is to summarize the key findings from genetic research, which show that autism is a complex disorder resulting from the combination of genetic and non genetic factors.
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    • "Moreover, recent studies have confirmed that LCLs preserve the inter-individual gene expression variability of primary B cells, including heritable patterns governed by genetic background [26], [27]. Despite the inherent limitations of research using transformed cell lines (reviewed in Welsh et al., 2009), it is increasingly recognized that LCLs derived from patient populations can be useful for studies of the effects of genetic variation on cellular function as related to disease and drug response [28]–[32]. Studies probing the regulatory functions of MS associated genomic regions have used genetic data from a LCL to demonstrate an overlap with B cell-specific transcriptionally active genomic regions [31], [32]. "
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    ABSTRACT: The effects of interferon-beta (IFN-β), one of the key immunotherapies used in multiple sclerosis (MS), on peripheral blood leukocytes and T cells have been extensively studied. B cells are a less abundant leukocyte type, and accordingly less is known about the B cell-specific response to IFN-β. To identify gene expression changes and pathways induced by IFN-β in B cells, we studied the in vitro response of human Epstein Barr-transformed B cells (lymphoblast cell lines-LCLs), and validated our results in primary B cells. LCLs were derived from an MS patient repository. Whole genome expression analysis identified 115 genes that were more than two-fold differentially up-regulated following IFN-β exposure, with over 50 previously unrecognized as IFN-β response genes. Pathways analysis demonstrated that IFN-β affected LCLs in a similar manner to other cell types by activating known IFN-β canonical pathways. Additionally, IFN-β increased the expression of innate immune response genes, while down-regulating many B cell receptor pathway genes and genes involved in adaptive immune responses. Novel response genes identified herein, NEXN, DDX60L, IGFBP4, and HAPLN3, B cell receptor pathway genes, CD79B and SYK, and lymphocyte activation genes, LAG3 and IL27RA, were validated as IFN-β response genes in primary B cells. In this study new IFN-β response genes were identified in B cells, with possible implications to B cell-specific functions. The study's results emphasize the applicability of LCLs for studies of human B cell drug response. The usage of LCLs from patient-based repositories may facilitate future studies of drug response in MS and other immune-mediated disorders with a B cell component.
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    • "In lymphocytes, we found that SLC6A4 expression was not changed in subjects with ASD. In contrast with our finding, Hu et al. previously reported that there was a significant decrease in the expression in the more severely affected twin for autistic twin pairs studied using lymphoblastoid cell lines [68]. This study used lymphoblastoid cell lines, not lymphocytes, from only three sets of discordant twins, and SLC6A4 expression was not compared with normal controls [68]. "
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    ABSTRACT: Changes in serotonin transporter (SERT) function have been implicated in autism. SERT function is influenced by the number of transporter molecules present at the cell surface, which is regulated by various cellular mechanisms including interactions with other proteins. Thus, we searched for novel SERT-binding proteins and investigated whether the expression of one such protein was affected in subjects with autism. Novel SERT-binding proteins were examined by a pull-down system. Alterations of SERT function and membrane expression upon knockdown of the novel SERT-binding protein were studied in HEK293-hSERT cells. Endogenous interaction of SERT with the protein was evaluated in mouse brains. Alterations in the mRNA expression of SERT (SLC6A4) and the SERT-binding protein in the post-mortem brains and the lymphocytes of autism patients were compared to nonclinical controls. N-ethylmaleimide-sensitive factor (NSF) was identified as a novel SERT-binding protein. NSF was co-localized with SERT at the plasma membrane, and NSF knockdown resulted in decreased SERT expression at the cell membranes and decreased SERT uptake function. NSF was endogenously co-localized with SERT and interacted with SERT. While SLC6A4 expression was not significantly changed, NSF expression tended to be reduced in post-mortem brains, and was significantly reduced in lymphocytes of autistic subjects, which correlated with the severity of the clinical symptoms. These data clearly show that NSF interacts with SERT under physiological conditions and is required for SERT membrane trafficking and uptake function. A possible role for NSF in the pathophysiology of autism through modulation of SERT trafficking, is suggested.
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