ArticleHuman molecular genetics2017
A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 104 citations in OpenAlex.
- Spinal muscular atrophy within Amish and Mennonite populations: Ancestral haplotypes and natural history.PloS one · 2018Trial
- The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.Biomolecules · 2026Review
- SMN deficiency inhibits endochondral ossification via promoting TRAF6-induced ubiquitination degradation of YBX1 in spinal muscular atrophy.Bone research · 2025Article
- Single NucleotideNeurology. Genetics · 2025Article
- Epigenetic regulation in spinal muscular atrophy: emerging areas and future directions.Orphanet journal of rare diseases · 2025Review
- Whole-transcriptome sequencing in neural and non-neural tissues of a mouse model identifies miR-34a as a key regulator in SMA pathogenesis.Molecular therapy. Nucleic acids · 2025Article
- Comprehensive analysis acrossiScience · 2025Article
- Frataxin: from the sequence to the biological role.Biophysical reviews · 2025Review
- Long-read sequencing identifies copy-specific markers of SMN gene conversion in spinal muscular atrophy.Genome medicine · 2025Article
- [Research progress on phenotypic modifier genes in spinal muscular atrophy].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2025Review
- Unraveling the genetic mysteries of spinal muscular atrophy in Chinese families.Orphanet journal of rare diseases · 2025Article
- Outcomes of a Pilot Newborn Screening Program for Spinal Muscular Atrophy in the Valencian Community.International journal of neonatal screening · 2025Article
- Onasemnogene-abeparvovec administration to premature infants with spinal muscular atrophy.Annals of clinical and translational neurology · 2024Article
- 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
- ComplexNeurology. Genetics · 2024Article
- 5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2.Journal of neurology · 2024Article
- Variants located in intron 6 ofHeliyon · 2024Article
- Specificity, synergy, and mechanisms of splice-modifying drugs.Nature communications · 2024Article
- Spinal muscular atrophy: Molecular mechanism of pathogenesis, diagnosis, therapeutics, and clinical trials in the Indian context.Journal of biosciences · 2024Review
3 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859G > C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6T transition, no other changes were detected. Analyzed with minigenes, SMN1C6T displayed a ∼20% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6. Using RNA-affinity chromatography and mass spectrometry, we further uncovered binding of the RNA-binding protein HuR to the -44 region, where it acts as a splicing repressor. The A-44G change markedly decreases the binding affinity of HuR, resulting in a moderate increase in exon 7 inclusion.
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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.