Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.
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.
Program in Neurogenetics, Department of Neurology and bfogel@ucla.edu.
Brent L
BL
Fogel
Program in Neurogenetics, Department of Neurology and.
Ellen
E
Cho
Program in Neurogenetics, Department of Neurology and.
Amanda
A
Wahnich
Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
Fuying
F
Gao
Radiation Biology and Oncology Laboratory, University of Queensland, UQ Centre for Clinical Research, Herston, Australia.
Olivier J
OJ
Becherel
Program in Neurogenetics, Department of Neurology and.
Xizhe
X
Wang
Department of Pathology and Laboratory Medicine and.
Francesca
F
Fike
Program in Neurogenetics, Department of Neurology and.
Leslie
L
Chen
Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
Chiara
C
Criscuolo
Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
Giuseppe
G
De Michele
Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy.
Alessandro
A
Filla
Department of Pediatrics and Department of Neurology, Children's Hospital Colorado, University of Colorado, Denver, School of Medicine, Aurora, CO, USA.
Abigail
A
Collins
Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada and.
Angelika F
AF
Hahn
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.
Richard A
RA
Gatti
Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Genevieve
G
Konopka
Program in Neurogenetics, Department of Neurology and.
Susan
S
Perlman
Radiation Biology and Oncology Laboratory, University of Queensland, UQ Centre for Clinical Research, Herston, Australia.
Martin F
MF
Lavin
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.
Daniel H
DH
Geschwind
Program in Neurogenetics, Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
Giovanni
G
Coppola
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D001072:Apraxias / Q000151:congenital; D001259:Ataxia / Q000097:blood / Q000235:genetics / Q000473:pathology*; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D055952:Cogan Syndrome / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D064251:Multifunctional Enzymes; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA
D064251:Multifunctional Enzymes; C484368:SETX protein, human; C581831:SETX protein, mouse; D004265:DNA Helicases; D020365:RNA Helicases