Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2

Fogel, Brent L., Cho, Ellen, Wahnich, Amanda, Gao, Fuying, Becherel, Olivier J., Wang, Xizhe, Fike, Francesca, Chen, Leslie, Criscuolo, Chiara, De Michele, Giuseppe, Filla, Alessandro, Collins, Abigail, Hahn, Angelika F., Gatti, Richard A., Konopka, Genevieve, Perlman, Susan, Lavin, Martin F., Geschwind, Daniel H. and Coppola, Giovanni (2014) Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2. Human Molecular Genetics, 23 18: 4758-4769. doi:10.1093/hmg/ddu190

Author Fogel, Brent L.
Cho, Ellen
Wahnich, Amanda
Gao, Fuying
Becherel, Olivier J.
Wang, Xizhe
Fike, Francesca
Chen, Leslie
Criscuolo, Chiara
De Michele, Giuseppe
Filla, Alessandro
Collins, Abigail
Hahn, Angelika F.
Gatti, Richard A.
Konopka, Genevieve
Perlman, Susan
Lavin, Martin F.
Geschwind, Daniel H.
Coppola, Giovanni
Title Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2014-04-23
Sub-type Article (original research)
DOI 10.1093/hmg/ddu190
Open Access Status
Volume 23
Issue 18
Start page 4758
End page 4769
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Collection year 2015
Language eng
Abstract 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
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Created: Thu, 16 Oct 2014, 10:29:25 EST by Olivier Becherel on behalf of School of Chemistry & Molecular Biosciences