ArticleProceedings of the National Academy of Sciences of the United States of America1999
A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02831296 (Prospective Evaluation of Infants With Spinal Muscular Atrophy), which is not on this map. Cited by 831 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Prospective Evaluation of Infants With Spinal Muscular Atrophy: SPOT SMA
Who cites it
831 citing papers in PubMed, 2 syntheses or guidelines pooled it, 1,534 citations in OpenAlex.
- Systematic Literature Review to Assess Economic Evaluations in Spinal Muscular Atrophy (SMA).PharmacoEconomics · 2022Pooled it
- Systematic Literature Review to Assess the Cost and Resource Use Associated with Spinal Muscular Atrophy Management.PharmacoEconomics · 2022Pooled it
- Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA).Journal of neurology · 2023Trial
- Nusinersen: the antisense oligonucleotide at the forefront of spinal muscular atrophy treatment.RNA biology · 2026Review
- Clinical Practice of Single-Molecule Real-Time Sequencing in the Diagnosis of Spinal Muscular Atrophy.Molecular genetics & genomic medicine · 2026Article
- Biphasic SMN condensates safeguard stress-induced cytoplasmic mislocalization of splicing RNPs.Cellular and molecular life sciences : CMLS · 2026Article
- Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons.Brain : a journal of neurology · 2026Article
- RNA-Based Therapeutics in Genetic Neurodevelopmental Disorders: Bridging Molecular Genetics and Precision Medicine.International journal of molecular sciences · 2026Review
- Survival Motor Neuron Protein Requirement-Supply Mismatch in Spinal Muscular Atrophy: A Conceptual Framework.Advances in therapy · 2026Review
- The splice of life: an isoform-centric view of disease, technology, and therapeutics.The Journal of clinical investigation · 2026Review
- Antisense oligonucleotides treatment uncovers differences in the modulation of dysregulated intracellular pathways in Spinal Muscular Atrophy motoneurons.Cell death & disease · 2026Article
- Phenotypic intrafamilial variability of 5q-associated spinal muscular atrophy: A systematic multicentre sibling study.Journal of neuromuscular diseases · 2026Article
- A p53-ΔNp73 signaling axis drives selective motor neuron degeneration in spinal muscular atrophy.bioRxiv : the preprint server for biology · 2026Article
- Longitudinal Transcriptomic Analysis Reveals Systemic Effects of Risdiplam in Adults with Spinal Muscular Atrophy.Brain sciences · 2026Article
- Smoking exposure alters splicing of the nicotinic acetylcholine receptor subunit CHRNA5.Human genomics · 2026Article
- Extracellular vesicles as biomarkers of disease progression and therapeutic response in patients with spinal muscular atrophy.Molecular therapy. Advances · 2026Article
- Flunarizine changes microRNA expression in cell cultures and in a mouse model of spinal muscular atrophy.Scientific reports · 2026Article
- Characterizing SMN1 hybrid and deletion alleles using large-scale SNP array-based SMA carrier screening.BMC medical genomics · 2026Article
- Tunable gene control via RNA splicing with a clinically approved small molecule.Nature communications · 2026Article
- Accessing medically relevant complex regions with a pangenome graph of 20 near-complete Japanese haplotypes.Nature communications · 2026Article
771 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNDelta7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.