Affinage

RAPSN

43 kDa receptor-associated protein of the synapse · UniProt Q13702

Length
412 aa
Mass
46.3 kDa
Annotated
2026-04-28
22 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Rapsyn (RAPSN) is a postsynaptic scaffold protein essential for clustering nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction (NMJ). It achieves this through liquid-liquid phase separation (LLPS) driven by multivalent tetratricopeptide repeat (TPR) domain interactions, forming condensates that recruit AChRs, cytoskeletal proteins, and signaling molecules, a process enhanced by MuSK signaling (PMID:34033754). Muscle-specific transcription of RAPSN depends on E-box elements in its promoter, and mutations disrupting these elements abolish allelic transcription and reduce rapsyn expression (PMID:12651869). Loss-of-function RAPSN mutations cause congenital myasthenic syndrome (CMS) with severity proportional to the degree of rapsyn loss, ranging from impaired AChR clustering and decreased miniature endplate potentials in partial loss to lethal fetal akinesia in complete loss (PMID:15036330, PMID:18179903).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1994 Medium

    Determining the genomic architecture of Rapsn established that the gene comprises 8 exons spanning ~12 kb, with exon-intron boundaries aligning to predicted structural domains, providing a framework for interpreting future mutations.

    Evidence Genomic cloning, RNase protection, and genetic mapping in mouse

    PMID:7698761

    Open questions at the time
    • No functional assays of individual domains performed
    • Human gene structure not yet characterized
  2. 1996 Medium

    Cloning the human RAPSN cDNA and mapping it to chromosome 11p11.2-p11.1 enabled subsequent mutation analysis in human neuromuscular disease.

    Evidence cDNA cloning, sequencing, somatic cell hybrid and radiation hybrid PCR mapping

    PMID:8812503

    Open questions at the time
    • No functional characterization of human rapsyn protein performed
  3. 2003 High

    Identifying that E-box elements in the RAPSN promoter are required for muscle-specific transcription revealed how rapsyn expression is restricted to the postsynaptic compartment and how promoter mutations cause rapsyn deficiency.

    Evidence EMSA, luciferase reporter assays in C2C12 myotubes and MyoD/myogenin-transfected HEK cells

    PMID:12651869

    Open questions at the time
    • In vivo consequences of promoter mutations on NMJ morphology not directly tested
    • Identity of specific transcription factors binding E-boxes not fully resolved
  4. 2004 Medium

    Electrophysiological demonstration that rapsyn-deficient patient endplates have decreased AChR density and reduced miniature endplate potential amplitude confirmed rapsyn's essential in vivo role in AChR clustering.

    Evidence Intercostal muscle biopsy with AChR quantification and miniature endplate potential recording from CMS patients

    PMID:15036330

    Open questions at the time
    • Mechanism by which rapsyn loss leads to AChR dispersal not addressed at a molecular level
    • Small number of patient biopsies
  5. 2006 Medium

    Showing that missense mutations R164C and L283P diminish rapsyn–AChR co-clustering identified specific residues required for the scaffolding interaction, while a splice-site mutation revealed an additional mechanism of rapsyn loss.

    Evidence Co-transfection clustering assay with mutant RAPSN constructs; minigene splicing analysis

    PMID:16931511

    Open questions at the time
    • Direct binding interface between rapsyn and AChR subunits not mapped
    • Structural basis of R164C and L283P defects not resolved
  6. 2008 Low

    Establishing that complete rapsyn loss causes lethal fetal akinesia while partial loss causes CMS defined a genotype–phenotype continuum and confirmed rapsyn as indispensable for NMJ formation.

    Evidence Genotype–phenotype correlation across RAPSN alleles of graded severity

    PMID:18179903

    Open questions at the time
    • No direct biochemical reconstitution of each allele's residual activity
    • Mechanism of fetal akinesia beyond NMJ failure not explored
  7. 2021 High

    Reconstituting rapsyn LLPS in vitro demonstrated that multivalent TPR-domain interactions drive phase separation to form condensates that recruit AChRs and associated proteins, providing the biophysical mechanism underlying postsynaptic clustering.

    Evidence In vitro LLPS reconstitution, live-cell imaging, co-condensation assays, mutagenesis, and mouse genetic model with CMS-associated LLPS-deficient mutation

    PMID:34033754

    Open questions at the time
    • How MuSK signaling biochemically modulates rapsyn LLPS (e.g., phosphorylation sites, kinetics) is not fully defined
    • Whether LLPS is the sole clustering mechanism or acts in concert with classical scaffolding interactions remains open

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the rapsyn–AChR interface, the precise post-translational modifications by which MuSK signaling potentiates rapsyn LLPS, and whether rapsyn condensates undergo regulated disassembly during synaptic remodeling remain unresolved.
  • No high-resolution structure of a rapsyn–AChR complex
  • Post-translational regulation of LLPS not mapped
  • Role of rapsyn in activity-dependent synaptic plasticity at the NMJ unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-1500931 Cell-Cell communication 2
Partners
CHRNA1MUSK

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Rapsyn undergoes liquid-liquid phase separation (LLPS) via multivalent binding of tetratricopeptide repeat (TPR) domains, forming liquid-like condensates that recruit acetylcholine receptors (AChRs), cytoskeletal proteins, and signaling proteins to establish the postsynaptic compartment of the neuromuscular junction (NMJ). MuSK signaling increases Rapsyn LLPS. CMS-associated mutations impair LLPS and co-condensation with interaction partners, and NMJ formation is disrupted in mice carrying a LLPS-deficient CMS mutation. In vitro LLPS reconstitution, live-cell imaging, co-condensation assays, mutagenesis of TPR domains, mouse genetic model with CMS-associated LLPS-deficient mutation Neuron High 34033754
2003 Two E-box mutations in the RAPSN promoter region (-27C→G and -38A→G) impair transcriptional regulation of RAPSN in muscle cells. The -27C→G mutation abolishes allelic transcription entirely; -38A→G alters nuclear protein binding affinity. Both mutations reduce luciferase reporter expression in C2C12 myotubes and MyoD/myogenin-transfected HEK cells, predicting reduced rapsyn expression and endplate AChR deficiency. Electrophoretic mobility shift assay (EMSA), luciferase reporter assay, transcriptional start site mapping, transfection in C2C12 and HEK cells Human molecular genetics High 12651869
2006 RAPSN missense mutations R164C and L283P diminish co-clustering of AChR with rapsyn, demonstrating that these residues are required for rapsyn-mediated AChR clustering at the postsynaptic membrane. A splice mutation (IVS1-15C>A) creates a novel acceptor splice site retaining 13 nucleotides of intron 1, causing a frameshift in the mature mRNA. Cotransfection of AChR subunits with mutant RAPSN constructs (in vitro clustering assay), RAPSN minigene transfection with RNA analysis for splice mutation Neurology Medium 16931511
1996 Human rapsyn is encoded by a 412-amino-acid cDNA showing 96% sequence identity with mouse rapsyn, and the RAPSN gene locus maps to chromosome 11p11.2-p11.1. cDNA cloning, sequencing, somatic cell hybrid and radiation hybrid PCR mapping Genomics Medium 8812503
1994 The mouse Rapsn gene spans ~12 kb and consists of 8 exons; exon-intron organization is consistent with structural domains predicted from amino acid sequence conservation, and the locus maps to the central region of mouse chromosome 2. Genomic cloning, RNase protection assay, sequence analysis of intron/exon boundaries, genetic mapping Genomics Medium 7698761
2008 A homozygous RAPSN frameshift mutation (c.1177-1178delAA) causes complete loss of rapsyn function resulting in lethal fetal akinesia sequence, while incomplete loss of rapsyn function (as seen with milder mutations) causes congenital myasthenia, establishing a genotype-phenotype continuum based on degree of rapsyn loss. Mutation analysis with functional interpretation; comparison of clinical severity across alleles with different predicted functional impact American journal of human genetics Low 18179903
2004 Rapsyn deficiency due to truncating/nonsense RAPSN mutations causes decreased AChRs per endplate and decreased amplitude of the miniature endplate potential, confirming rapsyn's essential role in clustering AChRs at the postsynaptic membrane in vivo. Intercostal muscle biopsy with AChR quantification and miniature endplate potential recording Neuromuscular disorders : NMD Medium 15036330
2012 A novel mutation (p.224 insT) in the TPR6 domain of RAPSN is associated with CMS, providing evidence that the TPR6 domain contributes to rapsyn self-association and co-clustering with AChR at the postsynaptic membrane. Mutation identification and domain analysis (genetic/structural inference) Journal of the neurological sciences Low 22326364

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. American journal of human genetics 81 18179903
2003 E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Human molecular genetics 77 12651869
2004 Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine. Neuromuscular disorders : NMD 37 15036330
2015 Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations. Neuromuscular disorders : NMD 31 26782015
2016 DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA. Oncotarget 30 27577081
2006 Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations. Neurology 29 16931511
2016 Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations. European journal of human genetics : EJHG 18 27966543
2017 Massive parallel sequencing identifies RAPSN and PDHA1 mutations causing fetal akinesia deformation sequence. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 17 28495245
2021 Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation. Neuron 16 34033754
2020 The Association Between RAPSN Methylation in Peripheral Blood and Early Stage Lung Cancer Detected in Case-Control Cohort. Cancer management and research 16 33173339
1996 Cloning of cDNA encoding human rapsyn and mapping of the RAPSN gene locus to chromosome 11p11.2-p11.1. Genomics 16 8812503
2018 Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil. Neuromuscular disorders : NMD 14 30266223
2010 Identification of previously unreported mutations in CHRNA1, CHRNE and RAPSN genes in three unrelated Italian patients with congenital myasthenic syndromes. Journal of neurology 14 20157724
2011 Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients. Muscle & nerve 12 21305573
2012 A novel mutation in the TPR6 domain of the RAPSN gene associated with congenital myasthenic syndrome. Journal of the neurological sciences 10 22326364
2010 Multiexon deletions account for 15% of congenital myasthenic syndromes with RAPSN mutations after negative DNA sequencing. Journal of medical genetics 9 20930056
1994 Characterization and mapping of the Rapsn gene encoding the 43-kDa acetylcholine receptor-associated protein. Genomics 8 7698761
2021 The association between RAPSN methylation in peripheral blood and breast cancer in the Chinese population. Journal of human genetics 5 33958711
2019 No Hot Spot Mutations CHRNE c.1327 delG, CHAT c.914T>C, and RAPSN c.264C>A in Iranian Patients with Congenital Myasthenic Syndrome. Iranian journal of child neurology 3 31037086
2021 Generation and characterization of an induced pluripotent stem cell line SDQLCHi018-A from a congenital myasthenic syndrome patient carrying compound heterozygote mutations in RAPSN gene. Stem cell research 1 33465529
2021 Clustering acetylcholine receptors in neuromuscular junction by phase-separated Rapsn condensates. Neuron 1 34139178
2024 Clinical and genetic diversity in Iranian individuals with RAPSN-related congenital myasthenic syndrome. Neurogenetics 0 39589458