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Series GSE61321 Query DataSets for GSE61321
Status Public on Sep 15, 2014
Title Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2 [02_fibroblasts_transfected]
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.
 
Overall design Total RNA samples obtained from 1) an AOA2 patient and carrier fibroblast cell lines, 2) 2 biological replicates of haploinsufficient SETX fibroblast cell lines transfected with one of 4 different wild-type and mutant SETX constructs, 3) peripheral blood from 33 patients and carriers across 12 families, and 4) 2 tissues from 2 Setx knockout and 2 control mice were analyzed using expression microarray.

This submission represents the microarray component of study.
 
Contributor(s) Fogel BL, Gao F, Becherel OJ, Lavin MF, Geschwind DH, Coppola G
Citation(s) 24760770
Submission date Sep 11, 2014
Last update date Mar 20, 2017
Contact name Brent L Fogel
E-mail(s) bfogel@ucla.edu
Organization name UCLA
Department Neurology
Street address 710 Westwood Plaza
City Los Angeles
State/province CA
ZIP/Postal code 90095
Country USA
 
Platforms (1)
GPL6883 Illumina HumanRef-8 v3.0 expression beadchip
Samples (16)
GSM1502040 G6407A_66B_af
GSM1502041 T5927G_68A_ca
GSM1502042 G6407A_66A_af
This SubSeries is part of SuperSeries:
GSE61400 Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2
Relations
BioProject PRJNA260981

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE61321_RAW.tar 3.9 Mb (http)(custom) TAR
GSE61321_non-normalized.txt.gz 2.3 Mb (ftp)(http) TXT
Processed data included within Sample table

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