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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Apraxias / congenital
  • Ataxia / blood
  • Ataxia / genetics
  • Ataxia / pathology*
  • Cell Line
  • Cerebellum / metabolism
  • Cogan Syndrome / genetics*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Humans
  • Mice
  • Multifunctional Enzymes
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • Sequence Analysis, RNA

Substances

  • Multifunctional Enzymes
  • SETX protein, human
  • SETX protein, mouse
  • DNA Helicases
  • RNA Helicases

Supplementary concepts

  • Apraxia, oculomotor, Cogan type