Affinage

CHN1

N-chimaerin · UniProt P15882

Length
459 aa
Mass
53.2 kDa
Annotated
2026-06-09
21 papers in source corpus 8 papers cited in narrative 8 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

CHN1 encodes alpha2-chimaerin, an SH2-domain-containing RacGAP that suppresses Rac signaling and governs ocular motor axon pathfinding (PMID:8336731, PMID:18653847). The purified protein hydrolyzes Rac-GTP in a reaction stimulated by phosphatidylserine, and its N-terminal SH2 domain binds phosphoproteins whose phosphorylation rises in response to trophic factors including NGF (PMID:8336731). Its C1 (phorbol ester/diacylglycerol) domain couples catalytic activity to subcellular localization, with C1 variants altering both Rac-GTP turnover and PMA-driven membrane translocation (PMID:33004823). Gain-of-function missense mutations that disrupt intramolecular contacts stabilizing the closed, autoinhibited conformation hyperactivate RacGAP activity, enhance membrane translocation and self-association/dimerization, and lower intracellular Rac-GTP, causing Duane retraction syndrome and related ocular motor nerve dysinnervation in human families and in chick and zebrafish models (PMID:18653847, PMID:21715346, PMID:21555619, PMID:37853116). In cancer, CHN1 is transcriptionally activated by TBX18 and increases RhoA activity to drive radioresistance, and its overexpression engages Akt/GSK-3β/Snail signaling to promote epithelial-mesenchymal transition (PMID:37399907, PMID:34238315).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1993 High

    Established alpha2-chimaerin's core biochemical identity: that the CHN1 splice product is a phosphatidylserine-stimulated RacGAP bearing an SH2 domain that reads trophic-factor-induced phosphorylation, linking it to Rac regulation downstream of signaling.

    Evidence Protein purification from rat brain plus recombinant assays for RacGAP activity, lipid stimulation, and SH2 phosphoprotein binding

    PMID:8336731

    Open questions at the time
    • Physiological SH2 ligands not molecularly identified
    • In vivo role of GAP activity not yet established
  2. 2008 High

    Connected CHN1 to human disease and defined the mechanism as gain-of-function: hyperactivating missense mutations enhance RacGAP activity, membrane translocation, and dimerization, and disrupt ocular motor axon innervation in vivo.

    Evidence In vitro RacGAP, translocation and self-association assays, in ovo chick mutant expression, and family genetic linkage

    PMID:18653847

    Open questions at the time
    • How excess RacGAP activity misroutes specific axons not resolved
    • Endogenous activators in motor neurons unknown
  3. 2011 High

    Extended the gain-of-function model by tying dimerization and membrane association directly to reduced cellular Rac-GTP, and broadened the clinical phenotype beyond classic Duane syndrome.

    Evidence Rac-GTP assay, translocation quantification, reciprocal co-IP for dimerization, and linkage analysis for the Y148F variant

    PMID:21715346

    Open questions at the time
    • Structural basis of dimer interface not determined
    • Phenotype-genotype correlation across variants unexplained
  4. 2011 Medium

    Identified the structural logic of hyperactivation, mapping mutations to residues stabilizing the inactive closed conformation, implying disruption of autoinhibition.

    Evidence Sequencing and structural modeling of intramolecular interactions for P141L and P252S

    PMID:21555619

    Open questions at the time
    • No direct enzymatic assay in this study
    • Closed-to-open transition not visualized structurally
  5. 2020 Medium

    Defined the C1 domain as a regulatory node controlling both catalysis and localization, showing a C1 variant can lower Rac-GTP yet still enhance PMA-induced translocation.

    Evidence Rac-GTP and PMA translocation assays plus co-IP in 293T cells with exome-identified p.Phe213Val

    PMID:33004823

    Open questions at the time
    • Single cell-line context
    • Relationship between C1 lipid sensing and SH2 input not integrated
  6. 2021 Medium

    Opened a cancer-relevant role distinct from neurodevelopment, showing CHN1 overexpression drives EMT via Akt/GSK-3β/Snail signaling.

    Evidence Overexpression/knockdown, EMT marker western blots, migration assays, xenograft, and PI3K inhibition with LY294002 in cervical carcinoma cells

    PMID:34238315

    Open questions at the time
    • Mechanistic link between RacGAP activity and Akt activation unresolved
    • Single tumor-type context
  7. 2023 Medium

    Placed CHN1 in a transcriptional axis promoting radioresistance, with TBX18 activating CHN1 and CHN1 increasing RhoA activity.

    Evidence Luciferase and ChIP for TBX18-promoter binding, GST pull-down for CHN1-RhoA, and knockdown/xenograft in esophageal squamous cell carcinoma

    PMID:37399907

    Open questions at the time
    • How a RacGAP elevates RhoA activity mechanistically not explained
    • Whether RhoA effect requires GAP catalysis untested
  8. 2023 Medium

    Confirmed in a second vertebrate model that disease variants impair ocular motor nerve development, strengthening the in vivo neurodevelopmental link.

    Evidence Whole exome sequencing and zebrafish mutant-mRNA injection imaging for p.His217Arg and p.Phe213Leu

    PMID:37853116

    Open questions at the time
    • Functional RacGAP consequences of these variants not assayed biochemically
    • Cellular target of axon misrouting not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same RacGAP reconciles its neurodevelopmental Rac-suppressing role with cancer-context RhoA activation and Akt signaling, and what its endogenous SH2 ligands and upstream activators are, remains unresolved.
  • No structure of the autoinhibited or active state
  • Endogenous SH2-binding phosphoproteins unidentified
  • Mechanistic basis for RhoA activation by a RacGAP unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
RAC1RHOATBX18

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Alpha2-chimaerin (CHN1) is an alternatively spliced product of the n-chimerin gene that contains an N-terminal SH2 domain in addition to phorbol ester receptor (C1) and GAP domains. The purified protein exhibits RacGAP activity that is stimulated by phosphatidylserine, and the SH2 domain binds phosphoproteins of PC12 cells whose phosphorylation increases in response to trophic factors including NGF. Protein purification from rat brain, in vitro RacGAP activity assay, recombinant E. coli protein assay, SH2 domain binding assay with 32P-labelled phosphoproteins Molecular and cellular biology High 8336731
2008 Missense mutations in CHN1 cause Duane's retraction syndrome (DURS2) via gain-of-function hyperactivation of alpha2-chimaerin RacGAP activity. Multiple mutations enhance alpha2-chimaerin translocation to the cell membrane and/or enhance self-association (dimerization). Expression of mutant alpha2-chimaerin in chick embryos causes failure of oculomotor axons to innervate target extraocular muscles. In vitro RacGAP activity assay, cell membrane translocation assay, self-association assay, in ovo chick embryo expression of mutant constructs, genetic linkage and mutation analysis in human families Science (New York, N.Y.) High 18653847
2011 A novel CHN1 mutation (Y148F) hyperactivates alpha2-chimaerin by enhancing its dimerization and membrane association, and lowers total intracellular Rac-GTP levels. This mutation causes vertical strabismus and supraduction deficits in addition to Duane retraction syndrome. Rac-GTP activation assay, alpha2-chimaerin translocation quantification, co-immunoprecipitation for dimerization, genetic linkage analysis Investigative ophthalmology & visual science High 21715346
2011 Two novel CHN1 mutations (P141L and P252S) alter residues that participate in intramolecular interactions stabilizing the inactive, closed conformation of alpha2-chimaerin, predicted to result in hyperactivation by disrupting autoinhibition. The same residue P252 was previously found mutated in another DRS pedigree, supporting a gain-of-function mechanism. DNA sequencing and mutation analysis, structural modeling of intramolecular interactions Archives of ophthalmology Medium 21555619
2020 A CHN1 variant (p.Phe213Val) in the C1 domain reduces Rac-GTP activity while enhancing membrane translocation in response to phorbol-myristoyl acetate (PMA), demonstrating that the C1 domain is critical for regulating both catalytic activity and subcellular localization of alpha2-chimaerin. Rac-GTP activation assay, alpha2-chimaerin translocation assay (PMA stimulation), co-immunoprecipitation, exome sequencing Scientific reports Medium 33004823
2023 TBX18 binds to the CHN1 promoter region to transcriptionally activate CHN1 expression, and elevated CHN1 increases RhoA activity (demonstrated by GST pull-down). This TBX18/CHN1/RhoA axis promotes radioresistance in esophageal squamous cell carcinoma cells. Dual-luciferase reporter assay, ChIP assay, GST pull-down for CHN1-RhoA interaction, ectopic expression/knockdown experiments in cells and xenograft mouse model Radiotherapy and oncology Medium 37399907
2021 CHN1 overexpression activates the Akt/GSK-3β/Snail signaling pathway to promote epithelial-mesenchymal transition (EMT) in cervical carcinoma cells, as demonstrated by increased phospho-Akt/phospho-GSK-3β, decreased epithelial markers, and increased mesenchymal markers; inhibition with LY294002 (PI3K inhibitor) blocked these effects. Overexpression and knockdown in cervical carcinoma cell lines, western blotting for EMT markers and pathway proteins, CCK-8/scratch/transwell assays, xenograft mouse model, pharmacological inhibition with LY294002 Journal of translational medicine Medium 34238315
2023 Two novel CHN1 variants (p.His217Arg and p.Phe213Leu) cause dysplasia of ocular motor nerves when expressed as mutant mRNAs injected into zebrafish embryos, confirming a role for CHN1 in ocular motor nerve development in a vertebrate in vivo model. Whole exome sequencing, zebrafish embryo mRNA injection with mutant CHN1 constructs, imaging of ocular motor nerve development Journal of human genetics Medium 37853116

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science (New York, N.Y.) 128 18653847
1993 Alpha 2-chimerin, an SH2-containing GTPase-activating protein for the ras-related protein p21rac derived by alternate splicing of the human n-chimerin gene, is selectively expressed in brain regions and testes. Molecular and cellular biology 81 8336731
2007 Magnetic resonance imaging evidence for widespread orbital dysinnervation in dominant Duane's retraction syndrome linked to the DURS2 locus. Investigative ophthalmology & visual science 80 17197533
2021 Candida albicans Isolates 529L and CHN1 Exhibit Stable Colonization of the Murine Gastrointestinal Tract. mBio 56 34724818
2011 Expansion of the CHN1 strabismus phenotype. Investigative ophthalmology & visual science 39 21715346
2020 Upregulation of miR-205 induces CHN1 expression, which is associated with the aggressive behaviour of cervical cancer cells and correlated with lymph node metastasis. BMC cancer 24 33109127
2011 Two novel CHN1 mutations in 2 families with Duane retraction syndrome. Archives of ophthalmology (Chicago, Ill. : 1960) 24 21555619
2007 Two pedigrees segregating Duane's retraction syndrome as a dominant trait map to the DURS2 genetic locus. Investigative ophthalmology & visual science 20 17197532
2021 CHN1 promotes epithelial-mesenchymal transition via the Akt/GSK-3β/Snail pathway in cervical carcinoma. Journal of translational medicine 15 34238315
2010 Analysis of the CHN1 gene in patients with various types of congenital ocular motility disorders. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 12 20535495
2021 CHN1 and duane retraction syndrome: Expanding the phenotype to cranial nerves development disease. European journal of medical genetics 6 33667650
2021 Bioinformatics-based analysis of the association between the A1-chimaerin (CHN1) gene and gastric cancer. Bioengineered 4 34152250
2020 Efficacy and Safety of Dulaglutide Monotherapy Compared to Glimepiride in Oral Antihyperglycemic Medication-Naïve Chinese patients with Type 2 Diabetes: A Post Hoc Analysis of AWARD-CHN1. Diabetes therapy : research, treatment and education of diabetes and related disorders 4 32219675
2020 Identification of a novel CHN1 p.(Phe213Val) variant in a large Han Chinese family with congenital Duane retraction syndrome. Scientific reports 4 33004823
2017 CHN1 gene mutation analysis in patients with Duane retraction syndrome. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus 4 29031989
2025 COL1A1, COL1A2, CHN1, and FN1 Promote Tumorogenesis and Act as Markers of Diagnosis and Survival in Gastric Cancer Patients. Current pharmaceutical biotechnology 3 39812067
2024 Case report: Identification of a novel variant p.Gly215Arg in the CHN1 gene causing Moebius syndrome. Frontiers in genetics 2 38356699
2023 TBX18 knockdown sensitizes esophageal squamous cell carcinoma to radiotherapy by blocking the CHN1/RhoA axis. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 1 37399907
2025 CHN1 as a potential predictive genetic biomarker for atopic dermatitis-related depression. Frontiers in immunology 0 41333466
2024 Special clinical features with a novel mutation site of CHN1 gene in a Chinese family with Duane retraction syndrome. Strabismus 0 38509018
2023 Two novel CHN1 variants identified in Duane retraction syndrome pedigrees disrupt development of ocular motor nerves in zebrafish. Journal of human genetics 0 37853116

Missed literature

Know a paper Affinage missed for CHN1? Flag it for the maintainers and the community.

No submissions yet.