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

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.

Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways

“…Of the several WGCNA studies reported utilizing expression data from patients with neurodegenerative disease, two of note in relation to our work are a WGCNA using data from brain and peripheral tissues of patients with ataxia with oculomotor apraxia type 2 (AOA2) and an analysis of brain expression data, including data from the cerebellum, from patients with C9orf72 associated and sporadic amyotrophic lateral sclerosis (ALS) (Fogel et al, 2014; Prudencio et al, 2015). AOA2 is due to recessive mutations in the Senataxin ( SETX ) gene while ALS4 is a juvenile form of ALS caused by dominant SETX mutations.…”

Termination of Transcription of Short Noncoding RNAs by RNA Polymerase II

“…An important future goal will be to identify the molecular defects that are associated with clinically relevant mutations in senataxin. Analysis of transcription in cells carrying AOA2- or ALS4-causing mutations revealed disease-specific effects on the expression of numerous genes (170). Providing molecular insight into some AOA2 mutations is the recent finding that a SUMOylation-mediated interaction between the N-terminal region of senataxin and the exosome protein Rrp45 is disrupted by AOA2-causing mutations in senataxin (171).…”

ZGRF1 variants implicated in a sensory reflex epilepsy

“…ZGRF1 also belongs to the family of UPF1-like RNA helicases that are involved in aspects of DNA replication and repair, transcription regulation, RNA metabolism, genome integrity or topoisomerase activities. Mutations in genes belonging to this family have been implicated in neurological conditions like distal spinal muscular atrophy (IGHMBP2; Grohmann et al, 2001), spinocerebellar ataxia and amyotrophic lateral sclerosis (SETX; Fogel et al, 2014).…”