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Global gene expression profile and splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells

ABSTRACT: Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Motoneurons derived from induced pluripotent stem cells (iPSC) obtained by reprogramming SMA patient and his healthy father fibroblasts, and genetically corrected SMA-iPSC obtained converting SMN2 into SMN1 with target gene correction (TGC), were used to study gene expression and splicing events linked to pathogenetic mechanisms. Microarray technology was used to assess the global gene expression profile as well as splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE27205 | GEO | 2013/01/04

SECONDARY ACCESSION(S): PRJNA141983

REPOSITORIES: GEO

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Global gene expression profile and splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells

Project description:Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Motoneurons derived from induced pluripotent stem cells (iPSC) obtained by reprogramming SMA patient and his healthy father fibroblasts, and genetically corrected SMA-iPSC obtained converting SMN2 into SMN1 with target gene correction (TGC), were used to study gene expression and splicing events linked to pathogenetic mechanisms. Microarray technology was used to assess the global gene expression profile as well as splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells. The microarray data derived from three different groups: SMA patient, healty father and treated SMA patient's cells. Each population consists of three RNA profiling cell samples.

2013-01-04 | E-GEOD-27205 | biostudies-arrayexpress

Global gene expression profiles of iPSC from SMA patient, unaffected father and iPS 19.9 compared to transcriptomic data obtained by corresponding fibroblasts

2013-01-04 | GSE27206 | GEO

Global gene expression profiles of iPSC from SMA patient, unaffected father and iPS 19.9 compared to transcriptomic data obtained by corresponding fibroblasts

Project description:Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Motoneurons derived from induced pluripotent stem cells (iPS cells) obtained by reprogramming SMA patient and his healthy father fibroblasts, and genetically corrected SMA-iPSC obtained converting SMN2 into SMN1 with target gene correction (TGC), were used to study gene expression and splicing events linked to pathogenetic mechanisms. Microarray technology was used to assess global gene expression profiles of iPSC from SMA patient, unaffected father and iPS 19.9 (Prof. J. Thomson's lab) compared to transcriptomic data obtained by corresponding fibroblasts. The microarray data derived from three different individuals: SMA patient, healthy father and control iPS cells (19.9). We analyzed iPSC from SMA patient (n=2), iPS- from healthy father (n=1) and iPS-19.9 from Prof. Thomson's lab (n=3). The expression profile was compared to SMA patient's fibroblasts (n=2) and healthy father's fibroblasts (n=1)

2013-01-04 | E-GEOD-27206 | biostudies-arrayexpress

Expression data from SMA fibroblasts treated with amiloride or EIPA

Project description:Spinal muscular atrophy (SMA) is an autosomal recessive, pediatric-onset disorder caused by the loss of spinal motor neurons thereby leading to generalized muscle atrophy. SMA is caused by the loss of or mutations in the survival motor neuron 1 (SMN1) gene. SMN1 is duplicated only in human to give rise to the paralogous SMN2 gene. These paralogs are nearly identical except for a cytosine to thymine (C-to-T) transition within an exonic splicing enhancer (ESE) element within exon 7. As a result, the majority of SMN2 transcripts lack exon 7 (SMNΔ7) which produces a truncated and unstable SMN protein. Since SMN2 copy number is inversely related to disease severity, it is a well-established target for SMA therapeutics development. 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of sodium/proton exchangers (NHEs), has previously been shown to increase exon 7 inclusion and SMN protein levels in SMA cells. In this study several different types of NHE inhibitors were evaluated for their ability to modulate SMN2 expression. EIPA as well as 5-(N,N-hexamethylene)amiloride (HMA) increase exon 7 inclusion in SMN2 splicing reporter lines as well as in SMA fibroblasts. The EIPA-induced exon 7 inclusion occurs via a mechanism unique from that used by RG7800, another SMN2 splicing modulator, and does not involve previously identified splicing factors. Transcriptome analysis identified novel targets, including TIA1 and FABP3, for further characterization. EIPA and HMA are more selective at inhibiting the NHE5 isoform, which is expressed in fibroblasts as well as in neuronal cells. These results show that NHE5 inhibition increases SMN2 expression and may be a novel target for therapeutics development.

2022-06-16 | GSE179861 | GEO

Analysis of splicing changes in motoneurons from mice of a severe model for Spinal Muscular Atrophy (SMA)

Project description:Motoneuron cell bodies were isolated by laser capture microdissection from severe SMA mice at postnatal day 3. The comparison was between heterozygote carriers, SMA disease mice and SMA mice rescued by a U7 snRNA correcting the splicing of human SMN2.

2015-03-05 | E-MTAB-3170 | biostudies-arrayexpress

The molecular bases of spinal muscular atrophy

Project description:Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the absence of a functional Survival of Motor Neuron 1 gene (SMN1). The nearly identical paralog, SMN2, cannot compensate for the loss of SMN1 because exon 7 is aberrantly skipped from most SMN2 transcripts, a process mediated by synergistic activities of Sam68/KHDR1 and hnRNP A1. This results in the production of a truncated, non-functional protein that is rapidly degraded. Here we present several crystal structures of Sam68 RNA-binding domain (RBD). Sam68-RBD forms stable symmetric homodimers by antiparallel association of helices α3 from two monomers. However, the details of domain organization and the dimerization interface differ significantly from previously characterized homologs. We demonstrate that Sam68 and hnRNP A1 bind proximal but distinct motifs within the central region of SMN2(ex7). Our findings have important implications for the etiology of SMA and open new avenues for the design of novel therapeutics to treat splicing diseases.

2024-05-23 | PXD033055 | Pride

Characterization of SMA Type II Skeletal Muscle from Treated Patients shows Mitochondrial Deficiency and Denervation

Project description:Spinal muscular atrophy (SMA) is a recessive, developmental disorder caused by the genetic loss or mutation of the gene SMN1 (Survival of Motor Neuron 1). SMA is characterized by neuromuscular symptoms and muscle weakness. Several years ago, SMA treatment underwent a radical transformation, with the approval of three different SMN-dependent disease modifying therapies. This includes two SMN2 splicing therapies - Risdiplam and Nusinersen. One main challenge for Type II SMA patients treated with these drugs is ongoing muscle fatigue, limited mobility, and other skeletal problems. To date, few molecular studies have been conducted on SMA-patient derived tissues after treatment, limiting our understanding of what targets remain after the principal spinal cord targeted therapies are applied. Therefore, we collected paravertebral muscle from eight Type II patients undergoing spinal surgery for scoliosis and seven controls. We used RNA-sequencing to characterize their transcriptional profiles and correlate these with muscle histology. Despite the limited cohort size and heterogeneity, we observed a consistent loss of oxidative phosphorylation machinery of the mitochondria, a decrease in mitochondrial DNA copy number, and a correlation between signals of cellular stress, denervation and increased fibrosis. This work provides new putative targets for combination therapies for Type II SMA.

2024-10-22 | GSE252128 | GEO

Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy

Project description:Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that, by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with nusinersen to promote E7 inclusion. Surprisingly, nusinersen promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to PolII elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the undesired chromatin effects of nusinersen, resulting in higher E7 inclusion, without large pleiotropic effects, as assessed by genome-wide analyses. Combined administration of nusinersen and VPA in SMA mice strongly synergized in SMN expression, growth, survival, and neuromuscular function.

2022-06-09 | GSE167762 | GEO

Homo sapiens

Project description:Global gene expression profile and splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells

| PRJNA141983 | ENA

Preliminary insights into RNA in CSF of SMA patients after Nusinersen “loading dose”

Project description:Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre–mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Since the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery.

2023-07-03 | GSE221900 | GEO

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