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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Daniel Schümperli

PROVIDER: E-MTAB-3170 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation.

Meyer Kathrin K Marquis Julien J Trüb Judith J Nlend Nlend Rachel R Verp Sonia S Ruepp Marc-David MD Imboden Hans H Barde Isabelle I Trono Didier D Schümperli Daniel D

Human molecular genetics 20081113 3

In spinal muscular atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilization of exon 7 and the production of functional protein. It has been hypothesized that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evide ...[more]

PMID: 19010792

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Gene Expression Analysis of spinal cord obtained from a mouse model of severe Spinal Muscular Atrophy (SMA)

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Transcription profiling of muscular and neuronal mouse mutant: spinal muscular atrophy(SMA)

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2005-05-20 | E-MEXP-131 | biostudies-arrayexpress

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

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2022-06-09 | GSE167762 | GEO

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

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