Mutation of Senataxin Alters Disease-Specific Transcriptional Networks in Patients with Ataxia with Oculomotor Apraxia Type 2 (P2.126)

Objective: To assess the functional role of senataxin in cerebellar and motor neuron disease pathogenesis through altered regulation of gene expression.Background: 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).Design/Methods: Genome-wide transcriptional microarray and RNA-sequencing was used to examine the effect of senataxin mutation on gene expression in cell lines and peripheral blood from AOA2 patients, transfected human cell lines, and Setx knockout mice.Results: 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.Conclusions: 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. Disclosure: Dr. Fogel has received personal compensation for activities with the American Physician Institute for Advanced Professional Studies. Dr. Fogel has received personal compensation in an editorial capacity for Neurologic Clinics. Dr. Cho has nothing to disclose. Dr. Wahnich has nothing to disclose. Dr. Gao has nothing to disclose. Dr. Becherel has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Fike has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Criscuolo has nothing to disclose. Dr. De Michele has nothing to disclose. Dr. Filla has nothing to disclose. Dr. Collins has nothing to disclose. Dr. Hahn has nothing to disclose. Dr. Gatti has nothing to disclose. Dr. Konopka has nothing to disclose. Dr. Perlman has received research support from Santhera Pharmaceuticals. Dr. Lavin has nothing to disclose. Dr. Geschwind has received personal compensation for activities with SynapDX, Allen Brain Institute, and Vanderbilt Kennedy Center. Dr. Coppola has nothing to disclose.