Affinage

SMN2

Survival motor neuron protein · UniProt Q16637

Length
294 aa
Mass
31.8 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMN2 is a near-identical paralog of SMN1 whose disease relevance in spinal muscular atrophy derives from a single C-to-T transition at exon 7 position +6 that causes most transcripts to skip exon 7 and produce an unstable, truncated SMNDelta7 isoform, while a minority of transcripts retain exon 7 to yield functional full-length SMN (PMID:10369862). The transition acts at the RNA level rather than through the essentially identical promoters (PMID:10366716): it simultaneously abolishes an SF2/ASF-dependent exonic splicing enhancer (PMID:16385450) and creates an exonic splicing silencer that recruits the repressor hnRNP A1, whose depletion restores exon 7 inclusion (PMID:12833158, PMID:17884807). Additional repression operates through tandem hnRNP A1/A2 motifs in the intron 7 ISS-N1 element (PMID:18371932), through Sam68/SAM68, which recruits hnRNP A1 and blocks U2AF65 at the exon 7 3' splice site (PMID:20186123, PMID:26438828), and through HuR binding near intron 6 position -44 (PMID:28460014), with reduced U2AF65 and U2 snRNP recruitment a key downstream consequence of the transition (PMID:19244360). Opposing these silencers, Htra2-beta1, hnRNP G and hnRNP M act on exon 7 enhancers to drive inclusion (PMID:10931943, PMID:24692659, PMID:24533984), while transcriptional activators such as ZPR1 raise overall SMN2 output (PMID:31828288). SMN2 copy number determines SMA severity because cumulative full-length SMN restores snRNP assembly, and SMN itself feeds back on snRNA levels to maintain efficient exon 7 splicing (PMID:10655541, PMID:20884664, PMID:19329542); SMN function in motor neurons is cell-autonomous (PMID:20826664). These mechanisms define the therapeutic strategy of redirecting SMN2 splicing toward full-length protein, achieved by ISS-N1-targeting antisense oligonucleotides (PMID:18371932, PMID:20624852) and by small-molecule modifiers that bind defined RNA elements (the exon 7 AGGAAG motif and the 5' splice-site TSL2 stem-loop) to stabilize U1 snRNP recognition and recruit activators such as FUBP1 and KHSRP (PMID:26030728, PMID:29712837, PMID:29795225).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 1999 High

    Established why SMN1 and SMN2 differ functionally despite sequence identity, pinpointing a single exon 7 nucleotide change as the cause of exon 7 skipping.

    Evidence Complete genomic sequencing and splicing assays comparing SMN1/SMN2 clones

    PMID:10369862

    Open questions at the time
    • The molecular identity of the disrupted enhancer/silencer factor was not resolved
    • Did not establish whether the effect was enhancer loss or silencer gain
  2. 1999 Medium

    Ruled out promoter/transcriptional differences as the explanation for SMN1-versus-SMN2 disease determination, focusing attention on post-transcriptional splicing.

    Evidence Parallel reporter assays of 750-bp 5'-flanking fragments in a motor neuron line

    PMID:10366716

    Open questions at the time
    • Reporter context may not capture native chromatin regulation
    • Modest 2-fold difference not functionally tested in vivo
  3. 2000 High

    Demonstrated that SMN dosage from SMN2 directly sets phenotypic severity in vivo, validating SMN2 as the disease-modifying gene and copy-number determinant.

    Evidence SMN2 transgene copy-number titration on a Smn-null mouse background with survival/histology

    PMID:10655541

    Open questions at the time
    • Did not resolve the splicing mechanism limiting full-length output
    • Mouse SMN2 expression may differ from human tissue distribution
  4. 2000 High

    Identified the first positive trans-acting regulator, showing exon 7 inclusion can be enhanced by an SR-like factor binding an exonic enhancer.

    Evidence Htra2-beta1 overexpression with SMN2 minigenes and RNA-binding assays

    PMID:10931943

    Open questions at the time
    • Did not establish whether endogenous Htra2-beta1 is rate-limiting in motor neurons
  5. 2003 Medium

    Provided early pharmacological proof that small molecules can raise full-length SMN2 output, linking it to Htra2-beta1 and transcriptional activation.

    Evidence Valproic acid treatment of SMA fibroblasts and rat brain slices with mRNA/protein readouts

    PMID:12915451

    Open questions at the time
    • Mechanism inferred, not directly demonstrated as causal
    • Magnitude of effect modest (2-4 fold)
  6. 2003 High

    Resolved the molecular consequence of the C-to-T change as creation of a silencer, identifying hnRNP A1 as the responsible repressor.

    Evidence Exon 7 mutagenesis, RNA-protein binding, and hnRNP A1 RNAi in cells

    PMID:12833158

    Open questions at the time
    • Did not reconcile with concurrent enhancer-loss models
    • Did not address intronic repressor contributions
  7. 2005 High

    Defined a parallel enhancer-loss mechanism (SF2/ASF-dependent ESE) and an hnRNP A/B antagonism common to both genes, broadening the regulatory model.

    Evidence Mutagenesis, RNAi, overexpression, and RNA-protein binding assays

    PMID:16385450

    Open questions at the time
    • Relative weight of ESE-loss versus ESS-gain left unsettled
  8. 2005 High

    Explained why residual SMNDelta7 is not entirely inert, showing it associates with and is stabilized by full-length SMN to partially ameliorate disease.

    Evidence SMNDelta7 transgenic crosses with survival and association assays

    PMID:15703193

    Open questions at the time
    • Quantitative contribution of stabilized SMNDelta7 to function not defined
  9. 2007 High

    Reinforced the silencer-centric model by showing hnRNP A1 binds SMN2 but not SMN1 exon 7 and that ASF/SF2 depletion does not alter splicing.

    Evidence Two independent hnRNP A1 depletion methods plus binding and splicing assays

    PMID:17884807

    Open questions at the time
    • Apparent conflict with ESE-loss model not fully reconciled
  10. 2008 High

    Identified the intron 7 ISS-N1 element and its tandem hnRNP A1/A2 motifs as a potent silencer, defining the highest-value antisense therapeutic target.

    Evidence ASO tiling, mutagenesis, RNA-affinity chromatography, and in vivo ASO delivery in mice

    PMID:18371932

    Open questions at the time
    • Long-term and clinical efficacy not addressed in this study
  11. 2008 High

    Implicated Sam68 as a repressor acting at the C-to-T site and showed dominant-negative Sam68 rescues SMN in patient cells.

    Evidence RNA pull-down, UV-crosslink, mutagenesis, and dominant-negative expression

    PMID:20186123

    Open questions at the time
    • In vivo relevance not yet tested at this stage
  12. 2008 Medium

    Added isoform-specific complexity by showing hnRNP Q1 promotes while Q2/Q3 antagonize exon 7 inclusion.

    Evidence Affinity chromatography, overexpression/knockdown, splicing assays in cells and mouse tissue

    PMID:18794368

    Open questions at the time
    • Single lab; physiological isoform balance in motor neurons unknown
  13. 2009 Medium

    Provided biochemical evidence that the C-to-T change weakens U2AF65 crosslinking and U2 snRNP recruitment, linking the silencer to early spliceosome assembly.

    Evidence UV crosslinking and native-gel U2 snRNP assembly in HeLa nuclear extract

    PMID:19244360

    Open questions at the time
    • In vitro extract may not reflect motor neuron context
  14. 2009 High

    Showed that correction of SMA correlates directly with snRNP assembly activity and that SMN2-derived SMN complements via heteromeric complexes.

    Evidence Transgenic rescue with snRNP assembly and snRNA assays in spinal cord

    PMID:19329542

    Open questions at the time
    • Whether snRNP assembly fully accounts for motor neuron pathology unresolved
  15. 2010 Medium

    Established a self-amplifying feedback loop in which low SMN reduces snRNA and further suppresses exon 7 inclusion, worsening deficiency.

    Evidence SMN depletion, snRNA measurement, and snRNP manipulation with splicing readout

    PMID:20884664

    Open questions at the time
    • Single lab; quantitative contribution of the loop to disease progression unknown
  16. 2010 High

    Demonstrated a cell-autonomous requirement for SMN in motor neurons, defining the relevant cellular target of SMN2-derived protein.

    Evidence Conditional SMN knockdown in motor neuronal progenitors with electrophysiology and NMJ analysis

    PMID:20826664

    Open questions at the time
    • Non-cell-autonomous contributions not excluded
  17. 2010 High

    Provided CNS proof-of-concept that ISS-N1 ASO delivery restores SMN in spinal motor neurons and rescues phenotype.

    Evidence ICV 2'-MOE ASO infusion and neonatal injection in SMA mice with mRNA/protein/phenotype readouts

    PMID:20624852

    Open questions at the time
    • Durability and systemic distribution not fully characterized here
  18. 2014 High

    Mapped the structural basis and trimeric complex (Tra2-beta1/hnRNP G/SRSF9) by which hnRNP G activates exon 7 inclusion.

    Evidence NMR structure of hnRNP G RRM bound to SMN2 RNA with mutagenesis and splicing assays

    PMID:24692659

    Open questions at the time
    • In vivo therapeutic relevance not tested
  19. 2014 Medium

    Identified hnRNP M as an enhancer-binding activator that recruits U2AF65 to promote exon 7 inclusion.

    Evidence Knockdown/overexpression, RNA-binding, and U2AF65 recruitment assays in patient cells

    PMID:24533984

    Open questions at the time
    • Single lab; in vivo role unknown
  20. 2014 Medium

    Identified PSF as a GAAGGA-enhancer-binding activator overlapping the Tra2-beta1 target.

    Evidence Overexpression/knockdown, enhancer mutagenesis, and RNA-binding assays

    PMID:24632473

    Open questions at the time
    • Single lab; physiological contribution unquantified
  21. 2014 High

    Confirmed Sam68's in vivo significance by showing genetic knockout enhances exon 7 inclusion and partially rescues SMA mice through impaired hnRNP A1 recruitment and U2AF65 displacement.

    Evidence SAM68 knockout in SMA mice with mechanistic splicing factor recruitment analysis

    PMID:26438828

    Open questions at the time
    • Only partial rescue; off-target Sam68 functions not dissected
  22. 2014 Medium

    Demonstrated an alternative RNA-based therapeutic using exon-specific U1 snRNAs that outperform ASOs by stabilizing pre-mRNA intermediates.

    Evidence ExSpe U1 expression, pre-mRNA stability assays, and AAV delivery in SMN2 transgenic mice

    PMID:25557785

    Open questions at the time
    • Single lab; clinical translatability not addressed
  23. 2015 High

    Revealed the core mechanism of small-molecule splicing modifiers: stabilizing the transient pre-mRNA/U1 snRNP duplex at the 5' splice site in a sequence-selective manner.

    Evidence Biochemical U1 snRNP binding, RNA structural analysis, and in vivo SMA mouse survival

    PMID:26030728

    Open questions at the time
    • Full set of recruited factors not yet defined at this stage
  24. 2017 High

    Identified HuR as an intron 6 (-44) repressor whose displacement by the A-44G change improves splicing.

    Evidence Minigene mutagenesis, RNA-affinity chromatography/MS, and splicing assays

    PMID:28460014

    Open questions at the time
    • Whether HuR can be therapeutically modulated not addressed
  25. 2017 High

    Showed risdiplam-class modifiers act by directly binding two distinct pre-mRNA sites and stabilizing a selective RNP rather than the general spliceosome.

    Evidence RNA/transcription/protein binding assays demonstrating direct pre-mRNA binding

    PMID:29133793

    Open questions at the time
    • Identity of all recruited factors not fully enumerated here
  26. 2018 High

    Defined the molecular details of modifier action, mapping binding to the exon 7 AGGAAG motif and identifying FUBP1 and KHSRP as recruited activators.

    Evidence Chemical proteomics, in vitro/in-cell SHAPE probing, and factor identification

    PMID:29712837

    Open questions at the time
    • Relative contributions of FUBP1 versus KHSRP not quantified
  27. 2018 High

    Established the TSL2 stem-loop at the 5' splice site as a druggable RNA conformational switch for enhancing exon 7 splicing.

    Evidence NMR/modelling of PK4C9-TSL2 complex with splicing rescue in SMA cells

    PMID:29795225

    Open questions at the time
    • In vivo efficacy of this chemotype not demonstrated
  28. 2012 Medium

    Linked environmental hypoxia to splicing repression via induction of hnRNP A1 and Sam68, with hyperoxia improving SMN2 inclusion in vivo.

    Evidence Cell hypoxia, minigene mutagenesis of hnRNP A1 sites, and hyperoxia treatment in SMA mice

    PMID:22763238

    Open questions at the time
    • Single lab; clinical relevance of oxygenation uncertain
  29. 2020 Medium

    Identified ZPR1 as a transcriptional/genome-stability regulator that raises SMN2 expression, rescues motor function, and reduces R-loop-associated DNA damage.

    Evidence RNA Pol II binding, ChIP at SMN locus, ZPR1 overexpression in SMA mice, and R-loop/DNA damage assays

    PMID:31828288

    Open questions at the time
    • Single lab; therapeutic feasibility of ZPR1 modulation untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many overlapping enhancer/silencer factors are integrated and prioritized in human motor neurons, and which are rate-limiting therapeutic targets, remains unresolved.
  • Quantitative hierarchy of trans-acting regulators in motor neurons unknown
  • Combinatorial logic linking splicing factor occupancy to exon 7 outcome undefined
  • Long-term durability of splice-redirecting therapies not established in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-74160 Gene expression (Transcription) 2
Partners
FUBP1HNRNP A1HNRNP GHTRA2-BETA1KHSRPSAM68SMN1U2AF65
Complex memberships
snRNP

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 A single C-to-T transition at position +6 in exon 7 is the critical difference between SMN1 and SMN2; this change causes the majority of SMN2 transcripts to skip exon 7, producing a shorter isoform, by disrupting an exonic splice enhancer activity. Complete genomic sequencing and comparison of SMN1 and SMN2 clones; splicing assays demonstrating differential exon 7 inclusion Human molecular genetics High 10369862
2000 Htra2-beta1, an SR-like splicing factor, promotes inclusion of SMN exon 7 by binding an AG-rich exonic splicing enhancer in SMN2 exon 7, thereby restoring full-length SMN2 expression. In vivo splicing assays with Htra2-beta1 overexpression in human and mouse cells carrying an SMN2 minigene; RNA-binding assays demonstrating direct interaction with the ESE Proceedings of the National Academy of Sciences of the United States of America High 10931943
2000 SMN2 transgene expression in Smn-null mice rescues embryonic lethality; one or two transgene copies produce severe SMA-like motor neuron loss, while eight copies rescue the phenotype, demonstrating that phenotypic severity is modulated by the level of SMN produced from SMN2. Transgenic mouse generation; crossing onto Smn-/- background; histological and survival analysis Human molecular genetics High 10655541
1999 The SMN1 and SMN2 gene promoters are nearly identical (~750 bp 5'-flanking region drives expression), with only a ~2-fold difference in reporter activity, ruling out promoter differences as the explanation for why SMN1 but not SMN2 is the disease-determining gene. Reporter construct transfection assays in motor neuron cell line using 750-bp 5'-flanking fragments from each gene Biochimica et biophysica acta Medium 10366716
2003 The C-to-T transition in SMN2 exon 7 creates an exonic splicing silencer (ESS) that functions as a binding site for hnRNP A1, which represses SMN2 exon 7 splicing; RNAi knockdown of hnRNP A1 in cells promotes efficient SMN2 exon 7 inclusion. Mutagenesis of exon 7; RNA-protein interaction assays; siRNA knockdown of hnRNP A1 in living cells with splicing readout Nature genetics High 12833158
2005 The C-to-T transition in SMN2 exon 7 results in loss of an SF2/ASF-dependent exonic splicing enhancer (ESE); hnRNP A/B proteins antagonize SF2/ASF-dependent ESE activity and promote exon 7 skipping independently of the C-to-T transition, representing a mechanism common to both SMN1 and SMN2. Mutagenesis, RNA interference, overexpression of splicing factors, RNA splicing assays, and RNA-protein interaction experiments American journal of human genetics High 16385450
2005 SMNDelta7 (the major SMN2 product lacking exon 7) associates with full-length SMN protein, and this association stabilizes SMNDelta7 and increases oligomeric SMN, ameliorating the SMA phenotype in transgenic mice. Transgenic mouse generation (SMNDelta7 crossed onto severe SMA background); survival analysis; co-immunoprecipitation/association assays Human molecular genetics High 15703193
2007 hnRNP A1 specifically binds SMN2 exon 7 (but not SMN1) and represses its splicing via the ESS mechanism; ASF/SF2 depletion does not affect SMN1/2 splicing, supporting the ESS-not-ESE model as primary mechanism. hnRNP A1 depletion by two independent methods; RNA-protein interaction assays; splicing assays Human molecular genetics High 17884807
2008 Two tandem hnRNP A1/A2 motifs in the intron 7 intronic splicing silencer (ISS-N1) repress SMN2 exon 7 inclusion; antisense oligonucleotides (ASOs) blocking these motifs promote very efficient exon 7 inclusion in transgenic mice in vivo. ASO tiling screen; mutagenesis; splicing assays; RNA-affinity chromatography; protein overexpression; in vivo ASO delivery in transgenic mice American journal of human genetics High 18371932
2008 Sam68 binds to the C-to-T transition-created binding site in SMN2 exon 7 (confirmed by RNA pull-down and UV-crosslink), triggers SMN2 exon 7 skipping, and dominant-negative Sam68 mutants that block hnRNP A1 recruitment enhance exon 7 inclusion and rescue SMN protein in SMA patient fibroblasts. RNA pull-down; UV crosslink; in vivo splicing assays; mutagenesis of Sam68 RNA-binding domain; retroviral dominant-negative mutant expression The EMBO journal High 20186123
2008 hnRNP Q isoforms differentially regulate SMN2 exon 7 splicing: the major isoform Q1 directly binds SMN exon 7 near position +6 and promotes exon 7 inclusion, while minor isoforms Q2/Q3 antagonize Q1 and induce exon 7 exclusion. Affinity chromatography; overexpression and knockdown of hnRNP Q isoforms; splicing assays in HeLa cells and testis of SMN2 transgenic mice Molecular and cellular biology Medium 18794368
2009 The C-to-T transition in SMN2 exon 7 reduces U2AF65 crosslinking and U2 snRNP association at the 3' splice site of intron 6 compared to SMN1, suggesting that differential U2 snRNP recruitment is a control point in SMN2 exon 7 splicing regulation. UV crosslinking of U2AF65; native gel electrophoresis of U2 snRNP assembly on SMN1 vs SMN2 RNAs; competition assays in HeLa nuclear extract RNA (New York, N.Y.) Medium 19244360
2010 SMN protein abundance positively feeds back on SMN2 exon 7 splicing: reduced SMN protein lowers cellular snRNA levels, which in turn decreases SMN2 exon 7 inclusion, creating a self-amplifying feedback loop that exacerbates SMN deficiency. SMN depletion in cells; measurement of snRNA levels; SMN2 splicing assays; manipulation of individual snRNP levels with functional readout Human molecular genetics Medium 20884664
2010 Selective SMN depletion in motor neuronal progenitors (but not abolition) is sufficient to cause an SMA-like phenotype with neuromuscular junction defects, motor neuron degeneration, and muscle atrophy in model mice expressing human SMN2, establishing a cell-autonomous role for SMN in motor neurons. Conditional SMN knockdown in motor neuronal progenitors using Cre-mediated approach in SMN2-expressing mice; electrophysiology; histology; NMJ analysis The Journal of neuroscience High 20826664
2010 Intracerebroventricular delivery of a 2'-MOE ASO targeting the ISS-N1 element in SMN2 intron 7 produces robust, long-lasting SMN2 exon 7 inclusion in spinal cord motor neurons at both mRNA and protein levels, and a single neonatal injection rescues tail and ear necrosis in SMA mice. Micro-osmotic pump ICV infusion; quantitative RT-PCR and immunoblot of spinal cord; neonatal ICV injection in SMA mice with phenotype rescue readout Genes & development High 20624852
2009 SMN(A111G), an allele competent for snRNP assembly, rescues SMA mice only when combined with SMN from SMN2, indicating that SMN(A111G) and SMN2-derived SMN undergo intragenic complementation in heteromeric complexes with higher snRNP assembly activity; correction of SMA correlates directly with snRNP assembly activity in spinal cord. Transgenic rescue experiments; snRNP assembly assays; snRNA level measurement in spinal cord of rescued vs unrescued mice Human molecular genetics High 19329542
2014 SAM68 binds SMN2 pre-mRNA and favors recruitment of the splicing repressor hnRNP A1 while interfering with U2AF65 binding at the 3' splice site of exon 7; genetic knockout of SAM68 promotes SMN2 exon 7 inclusion in SMA mice and partially rescues body weight, viability, and motor neuron/muscle defects. SAM68 knockout in SMA mouse model; SMN2 splicing assay; molecular mechanism by RNA-binding and spliceosome factor recruitment analysis The Journal of cell biology High 26438828
2014 hnRNP G binds to an SMN2 exon 7-derived RNA via its RRM domain interacting with a 5'-AAN-3' motif (specifically recognizing two consecutive adenines), and is recruited to a polyA tract upstream of the Tra2-beta1 binding site; this interaction, together with the RGG box, is required for hnRNP G to activate exon 7 inclusion as part of a Tra2-beta1/hnRNP G/SRSF9 trimeric complex. NMR structure of hnRNP G RRM bound to SMN2-derived RNA; mutagenesis of RRM and binding sites; splicing assays Nucleic acids research High 24692659
2014 hnRNP M binds an enhancer on SMN2 exon 7 (overlapping the Tra2-beta1 binding site) and promotes exon 7 inclusion by recruiting U2AF65 to the flanking intron; knockdown promotes exon 7 skipping and overexpression promotes inclusion in SMA patient cells. Knockdown and overexpression of hnRNP M; RNA-binding assays; U2AF65 recruitment assay; splicing assays in SMA patient cells Biochimica et biophysica acta Medium 24533984
2014 PSF (polypyrimidine tract-binding protein-associated splicing factor) binds the GAAGGA enhancer in SMN2 exon 7 and promotes exon 7 inclusion; mutation of this enhancer abolishes PSF's effect; PSF and Tra2-beta1 target partially overlapping sequences in exon 7. Overexpression and knockdown of PSF; mutagenesis of GAAGGA enhancer; RNA-protein interaction assays; splicing assays Biochimica et biophysica acta Medium 24632473
2015 Small-molecule SMN2 splicing modifiers stabilize the transient double-stranded RNA structure formed between the SMN2 pre-mRNA 5' splice site and U1 snRNP, increasing U1 snRNP binding affinity in a sequence-selective manner distinct from constitutive splicing recognition. Biochemical U1 snRNP binding assays; RNA structural analysis; in vitro and in vivo splicing assays; survival studies in severe SMA mouse model Nature chemical biology High 26030728
2017 The A-44G transition in SMN2 intron 6 improves exon 7 splicing by markedly decreasing binding of the RNA-binding protein HuR (which acts as a splicing repressor at the -44 region); identified by RNA-affinity chromatography and mass spectrometry combined with systematic mutagenesis. Minigene systematic mutagenesis; RNA-affinity chromatography; mass spectrometry identification of HuR; functional splicing assays Human molecular genetics High 28460014
2017 SMN2 splicing modifier small molecules (risdiplam class) directly bind to two distinct sites on the SMN2 pre-mRNA, stabilizing a ribonucleoprotein (RNP) complex that confers gene selectivity, rather than targeting the general splicing machinery. RNA splicing assays; transcription assays; protein chemistry; combination of RNA and protein binding techniques demonstrating direct pre-mRNA binding Nature communications High 29133793
2018 SMN-C2 and SMN-C3 (risdiplam analogs) directly bind the AGGAAG motif on SMN2 exon 7 pre-mRNA and promote a conformational change in unpaired nucleotides at the intron 6/exon 7 junction, creating a new binding surface that recruits FUBP1 and KHSRP to enhance SMN2 splicing. Chemical proteomics; SHAPE/structure probing of SMN2 pre-mRNA in vitro and in-cell; identification of recruited splicing factors FUBP1 and KHSRP Proceedings of the National Academy of Sciences of the United States of America High 29712837
2018 The stem-loop RNA structure TSL2 (overlapping the 5' splice site of SMN2 exon 7) is a drugable target; the small molecule PK4C9 binds pentaloop conformations of TSL2 and promotes a shift to triloop conformations that enhance exon 7 splicing, rescuing downstream molecular alterations in SMA cells. High-resolution NMR with molecular modelling of PK4C9-TSL2 complex; SMN2 splicing assays; SMA cell molecular rescue readouts Nature communications High 29795225
2003 Valproic acid increases full-length SMN2 mRNA and protein 2- to 4-fold in SMA patient fibroblasts, likely through elevation of Htra2-beta1 (which facilitates SMN2 exon 7 correct splicing) as well as through SMN gene transcription activation. Treatment of SMA patient fibroblast cultures with VPA; quantitative RT-PCR of SMN2 transcripts; western blot; immunofluorescence of gems; VPA treatment of rat hippocampal brain slices Human molecular genetics Medium 12915451
2012 Hypoxia increases hnRNP A1 and Sam68 levels in cells and promotes SMN2 exon 7 skipping; this hypoxia-induced skipping requires the SMN2 C>T mutation and is mediated through hnRNP A1 binding sites; hyperoxia treatment in SMA mice increases SMN2 exon 7 inclusion in skeletal muscle and improves motor function. Cell culture hypoxia treatment; SMN2 minigene splicing assays; mutation of hnRNP A1 binding sites; hyperoxia treatment in SMA mice with motor function readout Human molecular genetics Medium 22763238
2020 ZPR1 binds RNA polymerase II, interacts with the SMN locus in vivo, and upregulates SMN2 expression; ZPR1 overexpression in SMA mice increases systemic SMN levels, rescues motor function, and reduces neurodegeneration; ZPR1 also elevates senataxin levels, reduces R-loop accumulation, and rescues DNA damage in SMA. ZPR1-RNA Pol II binding assay; chromatin immunoprecipitation at SMN locus; ZPR1 overexpression in SMA mice; SMN level quantification; R-loop and DNA damage assays in patient cells and mice Brain : a journal of neurology Medium 31828288
2014 Exon-specific U1 snRNAs (ExSpe U1s) complementary to intronic sequences downstream of the SMN2 exon 7 5' splice site promote exon 7 inclusion and stabilize the SMN pre-mRNA intermediate, resulting in higher SMN mRNA levels than antisense oligonucleotides targeting the same intronic region; AAV-delivered ExSpe U1 increases exon 7 inclusion in multiple tissues of SMN2 transgenic mice. Integrated ExSpe U1 expression; pre-mRNA stability assay; comparison with ASO; AAV delivery in SMN2 transgenic mice with tissue-level splicing analysis American journal of human genetics Medium 25557785

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. American journal of human genetics 795 11791208
1999 A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Human molecular genetics 787 10369862
2000 The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. Human molecular genetics 600 10655541
2010 Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes & development 531 20624852
2005 SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Human molecular genetics 517 15703193
2008 Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. American journal of human genetics 479 18371932
1997 Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. American journal of human genetics 452 9199562
2003 A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nature genetics 448 12833158
2014 Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science (New York, N.Y.) 422 25104390
2018 Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). Journal of medicinal chemistry 408 30044619
2021 Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. The Lancet. Neurology 380 33743238
2018 Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscular disorders : NMD 350 29433793
2015 SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nature chemical biology 347 26030728
2003 Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Human molecular genetics 301 12915451
2007 Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS biology 281 17355180
2000 Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proceedings of the National Academy of Sciences of the United States of America 274 10931943
2002 Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genetics in medicine : official journal of the American College of Medical Genetics 270 11839954
2006 Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Human genetics 264 16508748
2005 Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2. American journal of human genetics 249 16385450
2001 SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Human genetics 188 11354640
2017 Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nature communications 166 29133793
2007 hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing. Human molecular genetics 151 17884807
2010 Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene. The Journal of neuroscience : the official journal of the Society for Neuroscience 131 20826664
2010 The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in spinal muscular atrophy. The EMBO journal 110 20186123
2018 Mechanistic studies of a small-molecule modulator of SMN2 splicing. Proceedings of the National Academy of Sciences of the United States of America 108 29712837
2006 The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Human genetics 101 16724231
2004 New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations. European journal of human genetics : EJHG 101 15470363
2002 Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity. Journal of neurology 100 12242541
2008 The RNA binding protein hnRNP Q modulates the utilization of exon 7 in the survival motor neuron 2 (SMN2) gene. Molecular and cellular biology 98 18794368
2003 Determination of SMN1 and SMN2 copy number using TaqMan technology. Human mutation 95 12815596
2018 Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). Journal of medicinal chemistry 94 30407821
1998 Correlation of SMNt and SMNc gene copy number with age of onset and survival in spinal muscular atrophy. European journal of human genetics : EJHG 94 9801871
2005 SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings. Journal of neurology 86 15981080
2017 A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Human molecular genetics 83 28460014
2009 A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice. Human molecular genetics 83 19329542
2005 Correction of SMN2 Pre-mRNA splicing by antisense U7 small nuclear RNAs. Molecular therapy : the journal of the American Society of Gene Therapy 83 16226920
2007 Restoration of SMN function: delivery of a trans-splicing RNA re-directs SMN2 pre-mRNA splicing. Molecular therapy : the journal of the American Society of Gene Therapy 74 17551501
2008 Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy. Journal of medicinal chemistry 72 18205293
2010 The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. Journal of medical genetics 71 20577007
2008 Development of a single vector system that enhances trans-splicing of SMN2 transcripts. PloS one 71 18941511
2006 SMN1 gene, but not SMN2, is a risk factor for sporadic ALS. Neurology 71 16931506
2019 Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype. Human genetics 70 30788592
2012 Homozygous SMN2 deletion is a major risk factor among twenty-five Korean sporadic amyotrophic lateral sclerosis patients. Yonsei medical journal 70 22187232
2010 A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Human molecular genetics 70 20884664
1999 Promoter analysis of the human centromeric and telomeric survival motor neuron genes (SMNC and SMNT). Biochimica et biophysica acta 70 10366716
2009 Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Science translational medicine 67 20161659
2023 Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing. American journal of human genetics 64 36669496
2013 Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. PloS one 64 23630626
1999 The promoters of the survival motor neuron gene (SMN) and its copy (SMNc) share common regulatory elements. American journal of human genetics 64 10205267
2006 Stimulating full-length SMN2 expression by delivering bifunctional RNAs via a viral vector. Molecular therapy : the journal of the American Society of Gene Therapy 62 16580882
2021 Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development. International journal of molecular sciences 61 34360669
2005 Quantitative analysis of SMN1 and SMN2 genes based on DHPLC: a highly efficient and reliable carrier-screening test. Human mutation 57 15832310
1999 Detection of the survival motor neuron (SMN) genes by FISH: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients. Human molecular genetics 57 10556301
2018 Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes. Nature communications 56 29795225
2018 Seamless Genetic Conversion of SMN2 to SMN1 via CRISPR/Cpf1 and Single-Stranded Oligodeoxynucleotides in Spinal Muscular Atrophy Patient-Specific Induced Pluripotent Stem Cells. Human gene therapy 54 29598153
2020 ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy. Brain : a journal of neurology 53 31828288
2020 Infants Diagnosed with Spinal Muscular Atrophy and 4 SMN2 Copies through Newborn Screening - Opportunity or Burden? Journal of neuromuscular diseases 52 32144995
2015 SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR. Molecular genetics & genomic medicine 52 26247043
2014 Improvement of SMN2 pre-mRNA processing mediated by exon-specific U1 small nuclear RNA. American journal of human genetics 51 25557785
2008 Combination of SMN2 copy number and NAIP deletion predicts disease severity in spinal muscular atrophy. Brain & development 51 18842367
2020 Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy. Neurology. Genetics 50 33324756
2014 Characterization of the RNA recognition mode of hnRNP G extends its role in SMN2 splicing regulation. Nucleic acids research 46 24692659
2013 Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients. Brain & development 42 24359787
2005 Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function? Journal of neuropathology and experimental neurology 42 15804053
2003 Inverse correlation between SMN1 and SMN2 copy numbers: evidence for gene conversion from SMN2 to SMN1. European journal of human genetics : EJHG 42 12673282
2013 Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy. Gene 39 23352792
2013 Pathological impact of SMN2 mis-splicing in adult SMA mice. EMBO molecular medicine 39 24014320
2012 Decreasing disease severity in symptomatic, Smn(-/-);SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery. Human gene therapy 39 22029744
2023 Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy. Nucleic acids research 38 37026480
2011 Generation and Characterization of a genetic zebrafish model of SMA carrying the human SMN2 gene. Molecular neurodegeneration 38 21443782
2014 hnRNP M facilitates exon 7 inclusion of SMN2 pre-mRNA in spinal muscular atrophy by targeting an enhancer on exon 7. Biochimica et biophysica acta 37 24533984
2020 Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells. Journal of neurochemistry 35 31811660
2004 Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells. European journal of human genetics : EJHG 35 15162126
2023 Optimization of base editors for the functional correction of SMN2 as a treatment for spinal muscular atrophy. Nature biomedical engineering 34 38057426
2021 Beyond copy number: A new, rapid, and versatile method for sequencing the entire SMN2 gene in SMA patients. Human mutation 34 33739559
2020 Discovery of a CNS penetrant small molecule SMN2 splicing modulator with improved tolerability for spinal muscular atrophy. Scientific reports 34 33060681
2009 Differential 3' splice site recognition of SMN1 and SMN2 transcripts by U2AF and U2 snRNP. RNA (New York, N.Y.) 34 19244360
2011 Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III. BMC medical genetics 32 21762474
2009 Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease. Acta biochimica Polonica 32 19287802
2015 Molecular characterization and copy number of SMN1, SMN2 and NAIP in Chinese patients with spinal muscular atrophy and unrelated healthy controls. BMC musculoskeletal disorders 31 25888055
2011 Correlation of SMN2, NAIP, p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 31 21821450
2022 Risdiplam: an investigational survival motor neuron 2 (SMN2) splicing modifier for spinal muscular atrophy (SMA). Expert opinion on investigational drugs 30 35316106
2016 Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy. Human molecular genetics 30 26931466
2015 Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7. Genomics 30 25645699
2008 SMN2 and NAIP gene dosages in Vietnamese patients with spinal muscular atrophy. Pediatrics international : official journal of the Japan Pediatric Society 30 18533950
2009 Splicing therapeutics in SMN2 and APOB. Current opinion in molecular therapeutics 29 19330716
2007 Genetic conversion of an SMN2 gene to SMN1: a novel approach to the treatment of spinal muscular atrophy. Experimental cell research 29 18078930
2011 Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines. Brain & development 27 21561730
2015 SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy. The Journal of cell biology 26 26438828
2008 Quantification of SMN1 and SMN2 genes by capillary electrophoresis for diagnosis of spinal muscular atrophy. Electrophoresis 26 18546169
2014 PSF contacts exon 7 of SMN2 pre-mRNA to promote exon 7 inclusion. Biochimica et biophysica acta 25 24632473
2013 Development and characterization of an SMN2-based intermediate mouse model of Spinal Muscular Atrophy. Human molecular genetics 24 23390132
2012 Homozygous SMN2 deletion is a protective factor in the Swedish ALS population. European journal of human genetics : EJHG 24 22274580
2012 Hypoxia is a modifier of SMN2 splicing and disease severity in a severe SMA mouse model. Human molecular genetics 24 22763238
2006 Determination of SMN1/SMN2 gene dosage by a quantitative genotyping platform combining capillary electrophoresis and MALDI-TOF mass spectrometry. Clinical chemistry 24 16439605
2024 Cognitive function in SMA patients with 2 or 3 SMN2 copies treated with SMN-modifying or gene addition therapy during the first year of life. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 23 38772209
2011 Identification of bidirectional gene conversion between SMN1 and SMN2 by simultaneous analysis of SMN dosage and hybrid genes in a Chinese population. Journal of the neurological sciences 23 21705024
2010 A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype. Human molecular genetics 23 20705738
2012 Identification of novel compounds that increase SMN protein levels using an improved SMN2 reporter cell assay. Journal of biomolecular screening 21 22233647
2021 Addressing Today's Absorption, Distribution, Metabolism, and Excretion (ADME) Challenges in the Translation of In Vitro ADME Characteristics to Humans: A Case Study of the SMN2 mRNA Splicing Modifier Risdiplam. Drug metabolism and disposition: the biological fate of chemicals 20 34620695

Missed literature

Know a paper Affinage missed for SMN2? Flag it for the maintainers and the community.

No submissions yet.