Affinage

SCNM1

Sodium channel modifier 1 · UniProt Q9BWG6

Length
230 aa
Mass
25.9 kDa
Annotated
2026-06-10
15 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SCNM1 is a C2H2 zinc finger protein that functions as an auxiliary RNA splicing factor, originally identified as a trans-acting modifier (Scnm1) that determines the efficiency with which a mutant splice donor site in Scn8a is correctly processed and thereby sets neurological disease severity in mice (PMID:9949206, PMID:12920299). It acts directly in splicing: it interacts with the spliceosomal protein U1-70K, co-immunoprecipitates with core Sm proteins, co-localizes with U1-70K in nuclear speckles, and shows activity in minigene splicing assays; its acidic C-terminal domain mediates interaction with LUC7L2, a factor implicated in recognition of non-consensus (weak) splice donor sites, and this domain is truncated by the R187X disease allele (PMID:17656373). Cryo-EM of the activated human minor spliceosome established SCNM1 as a bona fide minor-spliceosome component that structurally mimics the major-spliceosome SF3a complex to stabilize the catalytic center (PMID:33509932). Loss of SCNM1 function in human cells causes defective U12 (minor) intron splicing of a defined set of transcripts encoding primary cilia and basal body proteins, including TMEM107 and FAM92A, producing abnormally elongated primary cilia and impaired Hedgehog signaling, with wild-type SCNM1 re-introduction rescuing the defect (PMID:36084634); the C2H2 zinc finger domain is essential for this function (PMID:41291844). In hepatocellular carcinoma, SCNM1 is overexpressed via chromosome 1q copy-number gain and promotes tumor growth and apoptosis suppression through its splicing activity, regulating DERL2 and BAG6 (PMID:40172715).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 Medium

    Established that an unknown locus could act in trans to modify the phenotypic severity of a splice-site mutation, framing the question of how a single gene tunes splicing efficiency of another.

    Evidence Genetic mapping in an F2 mouse intercross linking Scnm1 alleles to Scn8a-dependent disease severity

    PMID:9949206

    Open questions at the time
    • Gene identity and molecular function not yet established
    • Mechanism of trans-modification unknown
    • No biochemical link to the spliceosome
  2. 2002 High

    Showed that the modifier acts quantitatively on splicing of the mutant Scn8a donor site, connecting reduced correctly-spliced mRNA to loss of Nav1.6 protein and electrophysiological/morphological deficits.

    Evidence RT-PCR transcript quantification, Western blot, nerve conduction velocity, and node-of-Ranvier morphology across modifier genotypes

    PMID:12374766

    Open questions at the time
    • Molecular identity of the modifier still unknown
    • Whether the effect is direct or indirect on splicing not resolved
  3. 2003 High

    Identified the modifier as SCNM1, a zinc finger putative splicing factor, and pinpointed the R187X nonsense allele as the susceptibility variant reducing functional SCNM1.

    Evidence Positional cloning and allele sequencing with transcript-level functional readout

    PMID:12920299

    Open questions at the time
    • Direct biochemical participation in splicing not yet demonstrated
    • Binding partners and spliceosomal context unknown
  4. 2007 High

    Demonstrated that SCNM1 physically engages the spliceosome and functions in splicing, mapping its LUC7L2 interaction to the C-terminal acidic domain lost in the disease allele.

    Evidence Yeast two-hybrid, Co-IP with Sm proteins, nuclear-speckle co-localization, minigene splicing assay, and domain-deletion mapping

    PMID:17656373

    Open questions at the time
    • Spliceosome (major vs minor) membership not structurally defined
    • Y2H/Co-IP interactions lack structural context
  5. 2008 High

    Confirmed in vivo that SCNM1 is a direct auxiliary splice factor with a specific, not global, effect on transcript processing.

    Evidence Targeted constitutive deletion allele with nuclear localization, Scn8a(medJ) splicing RT-PCR, and survey of other brain transcripts

    PMID:18791226

    Open questions at the time
    • Full repertoire of endogenous SCNM1-dependent splicing targets undefined
    • Mechanism of weak-donor recognition not resolved
  6. 2021 High

    Placed SCNM1 structurally within the activated minor spliceosome, revealing it mimics SF3a to stabilize the catalytic center.

    Evidence Cryo-EM of the human minor spliceosome at 2.9 Å with atomic modeling and comparison to major-spliceosome SF3a

    PMID:33509932

    Open questions at the time
    • Functional consequences of minor-spliceosome role in cells not yet linked to phenotype
    • Disease-relevant target genes not identified from structure alone
  7. 2022 High

    Connected SCNM1 loss to defective U12-intron splicing of cilia/basal-body genes, abnormal cilia, and impaired Hedgehog signaling, with rescue establishing causality.

    Evidence Patient fibroblasts, CRISPR knockout and siRNA in RPE-1 cells, RT-PCR/Western for U12 targets, cilia immunofluorescence, Hh signaling assay, and retroviral rescue

    PMID:36084634

    Open questions at the time
    • How specific U12 targets are selected by SCNM1 not defined
    • Mechanism linking cilia defect to Hh signaling step not fully resolved
  8. 2025 Medium

    Established the C2H2 zinc finger domain as essential for SCNM1 function via a pathogenic missense variant that fails to rescue.

    Evidence Exome sequencing, U12-target RT-PCR/Western in patient fibroblasts, cilia immunofluorescence, and rescue assay with mutant SCNM1

    PMID:41291844

    Open questions at the time
    • Single lab, limited replication
    • Biochemical role of the zinc finger in target/RNA recognition not directly tested
  9. 2025 Medium

    Extended SCNM1 function to oncogenic context, showing copy-number-driven overexpression promotes HCC growth and apoptosis suppression through its splicing activity.

    Evidence Colony formation and apoptosis assays, Western blot of DERL2/BAG6, RT-qPCR, and TCGA/GSE14520 correlation

    PMID:40172715

    Open questions at the time
    • Direct splicing mechanism on DERL2/BAG6 not demonstrated
    • Whether effect depends on minor-spliceosome activity unclear
    • Single lab, limited mechanistic depth

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SCNM1 recognizes non-consensus/weak splice donor sites and selects its specific minor-intron target repertoire across tissues remains the central open question.
  • No direct demonstration of SCNM1 RNA-binding specificity
  • Target selection rules unknown
  • Tissue-specific consequences of partial loss undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 3 GO:0003723 RNA binding 2
Localization
GO:0005654 nucleoplasm 2 GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-162582 Signal Transduction 1
Partners
LUC7L2SNRNP70
Complex memberships
minor spliceosome

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 A modifier locus (Scnm1) on mouse chromosome 3 was identified that determines the severity of the neurological phenotype caused by a splice site mutation in Scn8a; the C57BL/6J background (sensitive allele of Scnm1) results in lethal juvenile paralysis, while the C3H background (resistant allele) produces viable dystonic adults, establishing Scnm1 as a trans-acting modifier of Scn8a splicing efficiency. Genetic mapping in F2 intercross mice; phenotypic analysis of modifier-dependent disease severity Human molecular genetics Medium 9949206
2002 Scnm1 acts by modulating splicing efficiency at the mutant splice donor site of Scn8a(medJ); the sensitive (C57BL/6J) modifier allele reduces correctly spliced Scn8a mRNA to 5% of wild-type, whereas the resistant allele allows 10%, leading to near-complete loss of Nav1.6 protein, delayed maturation of nodes of Ranvier, and slowed nerve conduction velocity. RT-PCR quantification of correctly spliced transcripts; Western blotting for Nav1.6 protein; nerve conduction velocity measurement; morphological analysis of nodes of Ranvier Human molecular genetics High 12374766
2003 SCNM1 was identified as a zinc finger protein encoding a putative RNA splicing factor; the C57BL/6J susceptibility allele introduces a nonsense codon (R187X) into SCNM1, and an exon-skipping isoform due to disruption of a consensus exonic splicing enhancer is also predicted. Loss of full-length SCNM1 reduces correctly spliced Scn8a(medJ) transcripts below the survival threshold. Positional cloning; sequence analysis of SCNM1 alleles; comparison of correctly spliced Scn8a transcript levels between modifier genotypes Science (New York, N.Y.) High 12920299
2007 SCNM1 has a direct role in splicing: (1) SCNM1 protein interacts with the spliceosomal protein U1-70K in yeast two-hybrid assays; (2) SCNM1 co-localizes with U1-70K in nuclear speckles in mammalian cells; (3) SCNM1 co-immunoprecipitates with core spliceosomal Sm proteins; (4) SCNM1 shows functional splicing activity in a minigene assay; (5) SCNM1 interacts with LUC7L2 (a protein involved in recognition of non-consensus splice donor sites) via its acidic C-terminal domain, which is truncated by the disease allele SCNM1(R187X). Yeast two-hybrid screen; co-immunoprecipitation with Sm proteins; co-localization by immunofluorescence in mammalian cells; minigene splicing assay; domain-deletion analysis Human molecular genetics High 17656373
2008 A constitutive deletion of SCNM1 exons 3–5 (SCNM1Δ3-5) produces a protein that is correctly localized to the nucleus but is more functionally impaired than the C57BL/6J R187X allele in processing the Scn8a(medJ) transcript, confirming SCNM1's direct role as an auxiliary splice factor in vivo. Deficiency of SCNM1 did not broadly alter other brain transcripts tested. Targeted conditional knockout (floxed allele + Cre); nuclear localization by immunofluorescence; RT-PCR for Scn8a(medJ) splicing; transcript analysis of other brain genes Genetics High 18791226
2021 Cryo-EM structure of the activated human minor spliceosome at 2.9 Å resolution revealed that SCNM1 (a zinc finger protein) is a bona fide component of the minor spliceosome and functionally mimics the SF3a complex of the major spliceosome, stabilizing the conformation of the catalytic center. Cryo-electron microscopy at 2.9 Å resolution; atomic model building; structural comparison with major spliceosome SF3a Science (New York, N.Y.) High 33509932
2022 Loss of SCNM1 function in human cells (patient fibroblasts with bi-allelic SCNM1 mutations, CRISPR-Cas9 SCNM1 knockout RPE-1 cells, and SCNM1 siRNA-treated RPE-1 cells) causes defective minor intron (U12) splicing of a specific set of genes including TMEM107 (primary cilia protein) and FAM92A (basal body protein), resulting in abnormally elongated primary cilia and impaired Hedgehog signaling. Retroviral re-introduction of wild-type SCNM1 rescued cilia length, gene expression, and Hh signaling, establishing SCNM1 as a positive mediator of Hh signaling through its U12 intron splicing activity. Comparative transcriptome analysis of patient fibroblasts vs. controls; CRISPR-Cas9 knockout; siRNA knockdown; RT-PCR/Western blot for U12-intron containing genes; immunofluorescence for cilia length; Hedgehog signaling assay; retroviral rescue experiment American journal of human genetics High 36084634
2025 A missense variant in the C2H2 zinc finger domain of SCNM1, p.(His68Arg), causes loss of SCNM1 function: patient fibroblasts homozygous for this variant show diminished expression of U12-intron containing genes (TMEM107, CIBAR1) and abnormal primary cilia, and the mutant SCNM1(His68Arg) protein fails to rescue the phenotype of SCNM1-deficient cells, demonstrating that the C2H2 zinc finger domain is essential for SCNM1 function. Exome sequencing; RT-PCR/Western blot for U12-intron gene expression in patient fibroblasts; immunofluorescence for primary cilia; rescue assay with mutant SCNM1 in SCNM1-deficient cells Human genomics Medium 41291844
2025 In hepatocellular carcinoma cells, SCNM1 promotes tumor growth and suppresses apoptosis via its splicing activity, regulating downstream expression of DERL2 and BAG6 (proteins involved in protein degradation and apoptosis suppression); SCNM1 overexpression in HCC is driven by chromosome 1q copy number gain. Colony formation assay; apoptosis analysis; Western blotting for DERL2 and BAG6; RT-qPCR; correlation with SCNM1 expression in TCGA and GSE14520 datasets Annals of surgical oncology Medium 40172715

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 SCNM1, a putative RNA splicing factor that modifies disease severity in mice. Science (New York, N.Y.) 110 12920299
2002 Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). Human molecular genetics 89 12374766
2021 Structure of the activated human minor spliceosome. Science (New York, N.Y.) 73 33509932
1999 Dystonia associated with mutation of the neuronal sodium channel Scn8a and identification of the modifier locus Scnm1 on mouse chromosome 3. Human molecular genetics 62 9949206
2007 Evidence for a direct role of the disease modifier SCNM1 in splicing. Human molecular genetics 37 17656373
2003 TSRC1, a widely expressed gene containing seven thrombospondin type I repeats. Gene 27 12706885
2023 RNA Profiles of Tear Fluid Extracellular Vesicles in Patients with Dry Eye-Related Symptoms. International journal of molecular sciences 22 37895069
2022 Mutations in SCNM1 cause orofaciodigital syndrome due to minor intron splicing defects affecting primary cilia. American journal of human genetics 14 36084634
2022 Integrative Analysis of Nanopore and Illumina Sequencing Reveals Alternative Splicing Complexity in Pig Longissimus Dorsi Muscle. Frontiers in genetics 12 35480309
2003 High-resolution mapping of the sodium channel modifier Scnm1 on mouse chromosome 3 and identification of a 1.3-kb recombination hot spot. Genomics 12 13679025
2008 A targeted deleterious allele of the splicing factor SCNM1 in the mouse. Genetics 8 18791226
2015 Clinical and genetic analysis of a family with two rare reflex epilepsies. Seizure 6 26076849
2009 Regulation of IL2 and NUCB1 in mononuclear cells treated with acyl glucuronide of mycophenolic acid reveals effects independent of inosine monophosphate dehydrogenase inhibition. Therapeutic drug monitoring 3 19065122
2025 Clinical and Biological Significance of Sodium Channel Modifier 1 as a Component of the Minor Spliceosome in Hepatocellular Carcinoma. Annals of surgical oncology 1 40172715
2025 Expanding the phenotype associated with biallelic SCNM1 variants. Human genomics 0 41291844

Missed literature

Know a paper Affinage missed for SCNM1? Flag it for the maintainers and the community.

No submissions yet.