Description

Paralog of SMN1. Copy number is the primary modifier of SMA severity. C-to-T change in exon 7 causes ~90% exon skipping.

Function (UniProt)

The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs (PubMed:18984161, PubMed:9845364). Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core) (PubMed:18984161). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP (PubMed:18984161). To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate (PubMed:18984161). Within the SMN complex, SMN1 acts as a structural backbone and together with GEMIN2 it gathers the Sm complex subunits (PubMed:17178713, PubMed:21816274, PubMed:22101937). Binding of snRNA inside 5Sm ultimately triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP (PubMed:31799625). Ensures the correct splicing of U12 intron-containing genes that may be important for normal motor and proprioceptive neurons development (PubMed:23063131). Also required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination (PubMed:26700805). May also play a role in the metabolism of small nucleolar ribonucleoprotein (snoRNPs)

Linked hypotheses (20)

• SMN1 loss abolishes Sm ring ribonucleoprotein assembly, causing spliceosome dysfunction and motor neuron-selective mRNA processing failure that drives SMA pathology
  targetconf 98%
• SMN1 loss-of-function depletes functional SMN protein below a critical threshold, impairing snRNP biogenesis and splicing homeostasis in motor neurons, driving selective neurodegeneration in SMA
  targetconf 98%
• AAV9-mediated SMN1 gene replacement restores functional SMN protein complex assembly in motor neurons, rescuing snRNP biogenesis and splicing fidelity to prevent neurodegeneration in SMA
  targetconf 97%
• Correcting SMN2 exon 7 splicing via ISS-N1 blockade or small-molecule RNAP modulation restores functional SMN protein and rescues motor neuron survival in SMA
  targetconf 97%
• Restoration of SMN protein complex function rescues snRNP biogenesis and pre-mRNA splicing fidelity in motor neurons, reversing the core molecular pathology of SMA
  targetconf 97%
• SMN1 loss-of-function depletes functional SMN protein, disrupting snRNP biogenesis and axonal mRNA trafficking to drive anterior horn cell degeneration in SMA
  targetconf 97%
• SMN2 exon 7 splicing correction via small molecules or antisense oligonucleotides restores functional SMN protein above the pathological threshold, rescuing motor neuron survival in SMA
  targetconf 97%
• SMN1 loss-of-function depletes functional SMN protein below the threshold required for spliceosomal snRNP assembly, causing selective motor neuron degeneration that can be rescued by restoring SMN levels via gene replacement, splice-switching, or combinatorial approaches
  targetconf 95%
• SMN1 loss depletes functional SMN protein at motor neuron axons and neuromuscular junctions, causing SMA through impaired snRNP biogenesis and local mRNA translation, rescuable by SMN restoration via AAV9-mediated gene replacement or splice-switching ASOs
  targetconf 95%
• SMN2 exon-7 splicing correction via ASO, small molecule, or base editing restores full-length SMN protein above therapeutic threshold, reversing motor neuron degeneration in SMA
  targetconf 95%
• SMN2 exon 7 splicing correction via antisense oligonucleotide-mediated ISS-N1 blockade restores sufficient full-length SMN protein to prevent motor neuron degeneration in a copy-number-dependent manner
  targetconf 95%
• SMN2 copy number determines residual full-length SMN protein output via exon 7 inclusion frequency, creating a quantitative threshold that dictates motor neuron survival and SMA disease severity
  targetconf 95%
• SMN protein complex restoration via splicing modulation, ASO-mediated exon inclusion, or AAV9-mediated gene replacement rescues snRNP biogenesis and pre-mRNA splicing fidelity to halt SMA motor neuron degeneration
  targetconf 95%
• SMN complex insufficiency impairs Sm ring assembly onto pre-snRNAs, causing spliceosomal snRNP deficiency that selectively disrupts motor neuron transcriptome integrity and drives SMA neurodegeneration
  targetconf 95%
• [Drug Efficacy] DNMT3B is implicated in SMA pathogenesis based on 2 converging claims
  targetconf 94%
• [Splicing Event] SMN2 is implicated in SMA pathogenesis based on 165 converging claims
  targetconf 94%
• [Drug Target] SMN2 is implicated in SMA pathogenesis based on 139 converging claims
  targetconf 94%
• [Gene Expression] SMN2 is implicated in SMA pathogenesis based on 97 converging claims
  targetconf 94%
• [Survival] SMN2 is implicated in SMA pathogenesis based on 34 converging claims
  targetconf 94%
• [Motor Function] SMN2 is implicated in SMA pathogenesis based on 224 converging claims
  targetconf 93%

Top compound hits (10)

Linked claims (50)