Affinage

AP4M1

AP-4 complex subunit mu-1 · UniProt O00189

Length
453 aa
Mass
50.0 kDa
Annotated
2026-06-09
23 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AP4M1 encodes the mu (medium) subunit of a non-clathrin membrane coat adaptor complex, identified by homology to the medium chains of clathrin coat adaptors (PMID:9013859). In neurons it functions in intracellular trafficking required for dendritic compartmentalization: loss-of-function mutation produces aberrant localization of the GluRdelta2 glutamate receptor, abnormal dendritic spine morphology, and neuroaxonal degeneration (PMID:19559397). Biallelic loss-of-function variants abolish AP-4 complex function in patient-derived fibroblasts and cause the SPG50 form of hereditary spastic paraplegia (PMID:34087981). AAV-mediated delivery of AP4M1 restores AP-4 function in patient fibroblasts and achieves functional rescue in Ap4m1-knockout mice, establishing that AP4M1 is an essential, dose-limiting subunit of the complex (PMID:36951961). Beyond its role as an AP-4 subunit and its neuronal trafficking function, the molecular cargo-recognition mechanism of AP4M1 has not been further characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1997 Medium

    Established AP4M1 as a candidate coat-complex subunit, framing it as a mu-adaptin-related medium chain of a previously uncharacterized non-clathrin protein coat.

    Evidence cDNA cloning, primary structure and homology analysis, tissue distribution profiling

    PMID:9013859

    Open questions at the time
    • No demonstration that the protein assembles into a functional complex
    • No cargo or trafficking substrate identified
    • Function inferred only from sequence homology
  2. 2009 Medium

    Linked AP4M1 loss to a defined neuronal trafficking defect, showing the gene is required for correct localization of a specific glutamate receptor and for dendritic spine architecture.

    Evidence Homozygosity mapping with postmortem brain histology and immunohistochemistry in a patient with a splice-site loss-of-function mutation

    PMID:19559397

    Open questions at the time
    • Single case; causality not confirmed by rescue
    • Mechanism linking AP4M1 to GluRdelta2 trafficking not resolved
    • No direct cargo-binding evidence
  3. 2014 Low

    Characterized the normal dendritic distribution of AP4M1 and its loss/redistribution under ischemic stress, supporting a role in dendritic compartmentalization.

    Evidence Immunofluorescence, qPCR and western blotting in oxygen-glucose-deprived primary hippocampal neurons

    PMID:24486887

    Open questions at the time
    • Correlative localization data without functional rescue or epistasis
    • Single cell model
    • Does not establish trafficking mechanism
  4. 2020 Low

    Confirmed in independent patient cells that AP4M1 loss-of-function abolishes AP-4 complex function, reinforcing AP4M1 as an essential subunit.

    Evidence Functional studies in patient-derived fibroblasts carrying a splice variant

    PMID:33553621

    Open questions at the time
    • Single case report; mechanistic detail limited
    • AP-4 function readout not specified
    • No structural or cargo-level mechanism
  5. 2021 Low

    Provided further functional confirmation that biallelic AP4M1 variants cause loss of AP-4 function in SPG50 patient cells and generated iPSC resources for the disease.

    Evidence iPSC generation and functional characterization of patient-derived fibroblasts

    PMID:34087981

    Open questions at the time
    • Mechanistic details not elaborated
    • Single lab
    • Does not define molecular trafficking step disrupted
  6. 2023 High

    Demonstrated that restoring AP4M1 is sufficient to correct AP-4 dysfunction, providing causal proof that the gene's product is the limiting determinant of complex function in vitro and in vivo.

    Evidence AAV-mediated gene delivery with in vitro rescue in patient fibroblasts, in vivo rescue in Ap4m1-KO mice, and multi-species toxicology

    PMID:36951961

    Open questions at the time
    • Molecular cargo-recognition mechanism still not defined
    • Does not resolve which trafficking pathway step AP4M1 controls
    • Phenotypic readouts of rescue not mechanistically dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical mechanism by which AP4M1 recognizes cargo and the full set of trafficking substrates handled by the AP-4 complex remain undefined.
  • No structural model of AP4M1 within AP-4
  • Cargo-sorting motif specificity unknown
  • Trafficking itinerary (donor/acceptor compartments) uncharacterized in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 2
Complex memberships
AP-4 adaptor complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 AP4M1 (mu-ARP2) was identified as a novel mu-adaptin-related protein homologous to the medium chains of clathrin coat adaptor complexes, sharing 60% identity with mu-ARP1 and 27-31% identity with mu1/mu2-adaptins, suggesting it is a subunit of an uncharacterized non-clathrin protein coat involved in cellular membrane traffic. cDNA cloning, primary structure analysis, tissue distribution profiling FEBS letters Medium 9013859
2009 Loss-of-function mutation in AP4M1 (splice site mutation c.1137+1G>T in intron 14) causes neuroaxonal degeneration with aberrant GluRdelta2 glutamate receptor localization and abnormal dendritic spine morphology, establishing AP4M1's role in intracellular trafficking of glutamate receptors in neurons. Homozygosity mapping, RNA expression profiling, postmortem brain histology and immunohistochemistry American journal of human genetics Medium 19559397
2014 AP4M1 protein is normally distributed in the dendrites of hippocampal neurons; following oxygen-glucose deprivation, AP4M1 is downregulated at both mRNA and protein levels and redistributes from dendrites to axons, indicating a role in dendritic compartmentalization that is disrupted by ischemic injury. Immunofluorescence labeling, real-time PCR, western blotting in oxygen-glucose deprived primary hippocampal neurons Neuroscience letters Low 24486887
2021 Biallelic loss-of-function variants in AP4M1 (the mu subunit of adaptor protein complex 4) lead to loss of AP-4 complex function, as confirmed by functional studies in patient-derived fibroblasts from SPG50 patients. iPSC generation, functional characterization of patient-derived fibroblasts (AP-4 function assays) Stem cell research Low 34087981
2023 Transduction of SPG50 patient-derived fibroblasts with AAV2/AP4M1 rescues the AP-4 deficiency phenotype in vitro, and intrathecal delivery of AAV9/AP4M1 in Ap4m1-KO mice achieves dose- and age-dependent functional rescue, establishing that AP4M1 restoration is sufficient to correct AP-4 complex dysfunction. AAV-mediated gene delivery, in vitro phenotypic rescue in patient fibroblasts, in vivo KO mouse rescue studies, toxicology studies in rats and nonhuman primates The Journal of clinical investigation High 36951961
2020 Functional studies in patient-derived fibroblasts with a loss-of-function AP4M1 splice variant (c.59-1G>C) confirmed loss of adaptor protein complex 4 function, supporting AP4M1 as an essential subunit of the AP-4 complex. Functional studies in patient-derived fibroblasts Neurology. Genetics Low 33553621

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1989 The regulated production of mu m and mu s mRNA is dependent on the relative efficiencies of mu s poly(A) site usage and the c mu 4-to-M1 splice. Molecular and cellular biology 157 2565533
2009 Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. American journal of human genetics 141 19559397
2014 Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features. American journal of medical genetics. Part A 57 24700674
2002 Electronic structure description of the mu(4)-sulfide bridged tetranuclear Cu(Z) center in N(2)O reductase. Journal of the American Chemical Society 56 11817937
2002 Spectroscopic and electronic structure studies of the mu(4)-sulfide bridged tetranuclear Cu(Z) cluster in N(2)O reductase: molecular insight into the catalytic mechanism. Journal of the American Chemical Society 53 12197752
2023 Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. The Journal of clinical investigation 36 36951961
2014 A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency. BMC medical genetics 27 25496299
1997 Identification of two new mu-adaptin-related proteins, mu-ARP1 and mu-ARP2. FEBS letters 22 9013859
1964 CALCIUM ION REQUIREMENT FOR PROLIFERATION OF BACTERIOPHAGE PHI MU-4. Journal of bacteriology 22 14203343
1964 Isolation and preliminary characterization of bacteriophage phi-mu-4. Journal of bacteriology 20 5874550
1997 Domain-switched mouse IgM/IgG2b hybrids indicate individual roles for C mu 2, C mu 3, and C mu 4 domains in the regulation of the interaction of IgM with complement C1q. Journal of immunology (Baltimore, Md. : 1950) 15 9317134
2017 Severe congenital microcephaly with AP4M1 mutation, a case report. BMC medical genetics 10 28464862
2020 Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7. Neurology. Genetics 9 33553621
2014 AP4M1 is abnormally expressed in oxygen-glucose deprived hippocampal neurons. Neuroscience letters 5 24486887
2023 Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia. The journal of gene medicine 4 37758467
2021 Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4M1-associated hereditary spastic paraplegia (SPG50). Stem cell research 4 34087981
2012 catena-Poly[[[bis-[μ-3-(4-carb-oxy-phen-oxy)propionato]-κO,O:O;κO:O,O-bis-[aqua-(N,N-dimethyl-formamide-κO)cadmium]]-μ-4,4'-bipyridine-κN:N'] dinitrate]. Acta crystallographica. Section E, Structure reports online 1 22346877
1995 A monovalent C mu 4-specific ligand enhances the activation of human B cells by membrane IgM cross-linking ligands. International immunology 1 7734425
2026 A Novel AP4M1 Variant in an Iranian Child with Spastic Paraplegia 50: A Case Report and Molecular Docking Approach. Iranian journal of medical sciences 0 41625348
2013 The double-stranded ladder-like structure of poly[[bis(μ2-acetato-κ(2)O:O')bis(acetato-κO)bis(μ-4,4'-bipyridine-κ(2)N:N')dicopper(II)] 4-nitrophenol disolvate tetrahydrate]. Acta crystallographica. Section C, Crystal structure communications 0 24096493
2012 Decacarbon-yl[μ(4)-(ethane-1,2-diyl-dinitrilo)-tetra-kis-(methane-thiol-ato)]bis(triphenyl-phosphane)tetra-iron(2 Fe-Fe). Acta crystallographica. Section E, Structure reports online 0 22346806
2012 μ-4,4'-Bipyridine-κ2N:N'-bis[tetraaqua(4,4'-bipyridine-κN)dimanganese(II)] bis(4-aminobenzoate) bis(perchlorate)-4,4'-bipyridine-water (1/2/4): a supramolecular system constructed by π-π and hydrogen-bond interactions. Acta crystallographica. Section C, Crystal structure communications 0 22935493
2010 Poly[[tetraaquadi-μ(4)-glutarato-μ(2)-terephthalato-dineodymium(III)] heptadecahydrate]. Acta crystallographica. Section C, Crystal structure communications 0 21123880

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