Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of AOS Patient fibroblasts against Control fibroblasts

ABSTRACT: We described a striking divergence between the phenotypes arising from acute (siDOCK6) and chronic (DOCK6 KO cells) depletion is highly suggestive of a suppression mechanism that buffers the prolonged absence of DOCK6. This mechanism is probably also active in AOS patients who harbor homozygous loss-of-function mutations in DOCK6 because the actin organization patterns in their fibroblasts resemble those of DOCK6 KO cells (Shaheen et al., 2011). To identify the factor(s) that compensate for the lack of DOCK6 activity, we compared mRNA profiles of fibroblasts isolated from an AOS patient who harbored a homozygous 4 base pair deletion in the DOCK6 gene (c.1362_1365delAACT, p.Thr455Serfs*24; RefSeq accession number: NM_020812.2) with two healthy controls (Shaheen et al., 2011)

ORGANISM(S): Homo sapiens

SUBMITTER: Elmar Schiebel

PROVIDER: E-MTAB-5067 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The polyglutamine expansion in huntingtin (Htt) protein is a cause of Huntington’s disease (HD). Htt is an essential gene as deletion of the mouse Htt gene homolog (Hdh) is embryonic lethal in mice. Therefore, in addition to elucidating the mechanisms responsible for polyQ-mediated pathology, it is also important to understand the normal function of Htt protein for both basic biology and for HD. To systematically search for a mouse Htt function, we took advantage of the Hdh +/- and Hdh-floxed mice and generated four mouse embryonic fibroblast (MEF) cells lines which contain a single copy of the Hdh gene (Hdh-HET) and four MEF lines in which the Hdh gene was deleted (Hdh-KO). The function of Htt in calcium (Ca2+) signaling was analyzed in Ca2+ imaging experiments with generated cell lines. We found that the cytoplasmic Ca2+ spikes resulting from the activation of inositol 1,4,5-trisphosphate receptor (InsP3R) and the ensuing mitochondrial Ca2+ signals were suppressed in the Hdh-KO cells when compared to Hdh-HET cells. Furthermore, in experiments with permeabilized cells we found that the InsP3-sensitivity of Ca2+ mobilization from endoplasmic reticulum was reduced in Hdh-KO cells. These results indicated that Htt plays an important role in modulating InsP3R-mediated Ca2+ signaling. To further evaluate function of Htt, we performed genome-wide transcription profiling of generated Hdh-HET and Hdh-KO cells by microarray. Our results revealed that 106 unique transcripts were downregulated by more than two-fold with p < 0.05 and 173 unique transcripts were upregulated at least two-fold with p < 0.05 in Hdh-KO cells when compared to Hdh-HET cells. The microarray results were confirmed by quantitative real-time PCR for a number of affected transcripts. Several signaling pathways affected by Hdh gene deletion were identified from annotation of the microarray results. The unbiased approach used in our study provides novel and unique information about the normal function of Htt in cells, which may contribute to our understanding and treatment of HD. Keywords: cell type comparison we generate four Hdh-HET MEF cell lines and four Hdh-KO MEF cell lines, and performed genome-wide transcription profiling of generated Hdh-HET and Hdh-KO cells by microarray.

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Gene expression profiling of AOS Patient fibroblasts against Control fibroblasts

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