Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells

Boda, Bernadett; Mas, Christophe; Giudicelli, Catherine; Népote, Virginie; Guimiot, Fabien; Levacher, Béatrice; Zvara, Ágnes; Sántha, Miklós; LeGall, Isabelle; Simonneau, Michel

doi:10.1038/sj.ejhg.5201217

Cited by 37 publications

(41 citation statements)

References 43 publications

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“…TSS1b was mapped in Echaniz-Laguna et al [30], and TSS3 was identified in Monani et al, [31]. Nucleotide differences between the SMN1 and SMN2 promoters are indicated based on Monani et al, [31]; [29, 32]), where nucleotide positions were calculated from TSS1a. Translation initiation site is marked as Start.…”

Section: Figmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

112

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Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of SMN exon 7 splicing. There is evidence to support that multiple exons of SMN are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the SMN genes.

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Section: Figmentioning

confidence: 99%

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Singh

2018

Advances in Neurobiology

112

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“…Although SMN expression is ubiquitous, its expression is highest in the central nervous system (Fig. 2D) (25), particularly in spinal motor neurons where the disease is manifested (5,6,26). To assess the activity of RN-0005 in disease-relevant cells, we examined SMN expression in two neuronal cell types.…”

Section: Prc2mentioning

confidence: 99%

Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy

Woo

Maier

Davey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in SMN1 (Survival Motor Neuron 1). The disease severity inversely correlates with the copy number of SMN2, a duplicated gene that is nearly identical to SMN1. We have delineated a mechanism of transcriptional regulation in the SMN2 locus. A previously uncharacterized long noncoding RNA (lncRNA), SMN-antisense 1 (SMN-AS1), represses SMN2 expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction between SMN-AS1 and PRC2 inhibit the recruitment of PRC2 and increase SMN2 expression in primary neuronal cultures. Our approach comprises a gene-up-regulation technology that leverages interactions between lncRNA and PRC2. Our data provide proof-of-concept that this technology can be used to treat disease caused by epigenetic silencing of specific loci.spinal muscular atrophy | lncRNA | PRC2 | SMN S pinal muscular atrophy is the leading genetic cause of infant mortality and is caused by deletions or mutation of Survival Motor Neuron 1 (SMN1) (1). Unique to humans, SMN1 is duplicated in the genome as SMN2, which is nearly identical in sequence. However, a C-to-T point mutation in exon 7 of SMN2 results in preferential skipping of this exon during pre-mRNA splicing and production of a truncated and unstable protein. A small fraction (10-20%) of pre-mRNA transcribed from SMN2 is spliced correctly to include exon 7 and produces a full-length SMN (SMN-FL, inclusive of exon 7) that is identical to the SMN1 gene product (2-4).Spinal motor neurons are highly sensitive to SMN1 deficiency, and their premature death causes motor function deficit in SMA patients (5, 6). The SMN2-derived SMN protein can extend spinal motor neuron survival, yet insufficient levels of SMN eventually lead to cell death. Overall, SMA patients with higher SMN2 genomic copy number have a less severe disease phenotype (7, 8). Type 0 or I patients, carrying one or two copies of SMN2, show onset of SMA within a few months of life with a life expectancy of less than 2. In contrast, type III and IV patients, carrying three or more copies, respectively, show juvenile or adult onset and slower disease progression (9). As further genetic evidence, SMA mouse models have been produced in which smn1 −/− mice, which would otherwise be embryonic lethal (10), can be rescued in the presence of high copy numbers of the human SMN transgene (11-13). Similar to the human disease spectrum, increased copy number of a human SMN transgene is inversely associated with decreased disease severity and mortality. We reasoned that increasing SMN2 transcription could phenocopy the beneficiary effect of SMN2 gene amplification and compensate for SMN1 deficiency. In addition, SMN1 heterozygotes are asymptomatic, whereas affected homozygotes have 10-20% of normal SMN levels. Therefore, we predict that modest SMN2 up-regulation will provide significant therapeutic benefit. H...

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“…Interestingly, the highest levels of SMN are detected in the ventral horn of the spinal cord and motor neurons [41,71], which are primarily affected in SMA. Accordingly, the strongest decline of SMN levels in SMA is also observed in these tissues [74]. Changes in gene expression patterns during development have previously been linked to epigenetic regulation [75].…”

Section: Hdac Inhibitors In Sma Treatmentmentioning

confidence: 81%

Applicability of Histone Deacetylase Inhibition for the Treatment of Spinal Muscular Atrophy

Lunke

El‐Osta

2013

Neurotherapeutics

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Spinal muscular atrophy (SMA), a neurodegenerative disease with potentially devastating and even deadly effects on affected individuals, was first described in the late nineteenth century. Although the survival of motor neuron (SMN) gene was identified nearly 2 decades ago to be causative of the disease, neither an effective treatment nor a cure are currently available. Yet efforts are on-going to test a multitude of treatment strategies with the potential to alleviate disease symptoms in human and clinical trials. Among the most studied compounds for the treatment of SMA are histone deacetylase inhibitors. Several of these epigenetic modifiers have been shown to increase expression of the crucial SMN gene in vitro and in vivo, an effect linked to increased histone acetylation and remodeling of the chromatin landscape surrounding the SMN gene promoter. Here, we review the history and current state of use of histone deacetylase inhibitors in SMA, as well as the success of clinical trials investigating the clinical applicability of these epigenetic modifiers in SMA treatment.

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Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells

Cited by 37 publications

References 43 publications

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy

Applicability of Histone Deacetylase Inhibition for the Treatment of Spinal Muscular Atrophy

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