Expression data from SMA fibroblasts treated with amiloride or EIPA

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179861 | GEO | 2022/06/16

REPOSITORIES: GEO