ArticleHuman molecular genetics2009
Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition.
Article in Human molecular genetics, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers, 2 of them syntheses that pooled it.
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Who cites it
71 citing papers in PubMed, 2 syntheses or guidelines pooled it, 138 citations in OpenAlex.
- Drug treatment for spinal muscular atrophy types II and III.The Cochrane database of systematic reviews · 2020Pooled it
- Drug treatment for spinal muscular atrophy type I.The Cochrane database of systematic reviews · 2019Pooled it
- A Comparative Study of SMN Protein and mRNA in Blood and Fibroblasts in Patients with Spinal Muscular Atrophy and Healthy Controls.PloS one · 2016Trial
- Comparative Analysis ofBiomedicines · 2026Article
- Survival Motor Neuron Protein Requirement-Supply Mismatch in Spinal Muscular Atrophy: A Conceptual Framework.Advances in therapy · 2026Review
- Therapeutic strategies for spinal muscular atrophy: the history and future perspective.Frontiers in human neuroscience · 2026Review
- Target-Based Discovery of Drug Combinations for Spinal Muscular Atrophy.Advances in experimental medicine and biology · 2026Article
- Histone Deacetylase 2 in Alzheimer's Disease: A Comprehensive Molecular Blueprint for Therapeutic Targeting.Molecular neurobiology · 2025Review
- Epigenetic regulation in spinal muscular atrophy: emerging areas and future directions.Orphanet journal of rare diseases · 2025Review
- Comprehensive analysis acrossiScience · 2025Article
- Long-read sequencing identifies copy-specific markers of SMN gene conversion in spinal muscular atrophy.Genome medicine · 2025Article
- The Relevance of Spinal Muscular Atrophy Biomarkers in the Treatment Era.Biomedicines · 2024Review
- In Search of Spinal Muscular Atrophy Disease Modifiers.International journal of molecular sciences · 2024Review
- Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases.Signal transduction and targeted therapy · 2024Review
- Recent Progress in Gene-Targeting Therapies for Spinal Muscular Atrophy: Promises and Challenges.Genes · 2024Review
- Cognitive impairment in children with 5q-associated spinal muscular atrophy type 1: two case reports and the review of the literature.Frontiers in pediatrics · 2024Article
- Association among biomarkers, phenotypes, and motor milestones in Chinese patients with 5q spinal muscular atrophy types 1-3.Frontiers in neurology · 2024Article
- PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice.EMBO molecular medicine · 2023Article
- Innovating spinal muscular atrophy models in the therapeutic era.Disease models & mechanisms · 2023Article
- Identifying Biomarkers of Spinal Muscular Atrophy for Further Development.Journal of neuromuscular diseases · 2023Article
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spinal muscular atrophy (SMA), a common neuromuscular disorder, is caused by homozygous absence of the survival motor neuron gene 1 (SMN1), while the disease severity is mainly influenced by the number of SMN2 gene copies. This correlation is not absolute, suggesting the existence of yet unknown factors modulating disease progression. We demonstrate that the SMN2 gene is subject to gene silencing by DNA methylation. SMN2 contains four CpG islands which present highly conserved methylation patterns and little interindividual variations in SMN1-deleted SMA patients. The comprehensive analysis of SMN2 methylation in patients suffering from severe versus mild SMA carrying identical SMN2 copy numbers revealed a correlation of CpG methylation at the positions -290 and -296 with the disease severity and the activity of the first transcriptional start site of SMN2 at position -296. These results provide first evidence that SMN2 alleles are functionally not equivalent due to differences in DNA methylation. We demonstrate that the methyl-CpG-binding protein 2, a transcriptional repressor, binds to the critical SMN2 promoter region in a methylation-dependent manner. However, inhibition of SMN2 gene silencing conferred by DNA methylation might represent a promising strategy for pharmacologic SMA therapy. We identified histone deacetylase (HDAC) inhibitors including vorinostat and romidepsin which are able to bypass SMN2 gene silencing by DNA methylation, while others such as valproic acid and phenylbutyrate do not, due to HDAC isoenzyme specificities. These findings indicate that DNA methylation is functionally important regarding SMA disease progression and pharmacological SMN2 gene activation which might have implications for future SMA therapy regimens.
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