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Hum Mol Genet. 2014 Sep 15;23(18):4758-69. doi: 10.1093/hmg/ddu190. Epub 2014 Apr 23.

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

Author information

1
Program in Neurogenetics, Department of Neurology and bfogel@ucla.edu.
2
Program in Neurogenetics, Department of Neurology and.
3
Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
4
Radiation Biology and Oncology Laboratory, University of Queensland, UQ Centre for Clinical Research, Herston, Australia.
5
Department of Pathology and Laboratory Medicine and.
6
Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
7
Department of Pediatrics and Department of Neurology, Children's Hospital Colorado, University of Colorado, Denver, School of Medicine, Aurora, CO, USA.
8
Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada and.
9
Department of Pathology and Laboratory Medicine and Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
10
Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
11
Program in Neurogenetics, Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
12
Program in Neurogenetics, Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.

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.

PMID:
24760770
PMCID:
PMC4140459
DOI:
10.1093/hmg/ddu190
[Indexed for MEDLINE]
Free PMC Article
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