AP4E1 Gene

Name	adaptor-related protein complex 4, epsilon 1 subunit
Description	This gene encodes a member of the adaptor complexes large subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is a large subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Disruption of this gene may be associated with cerebral palsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n AP4E1 encodes the ε‐subunit of the heterotetrameric adaptor protein complex‐4 (AP‐4), which plays a pivotal role in sorting transmembrane cargo from the trans‐Golgi network to endosomal compartments. Disruption of AP4E1 compromises the assembly and function of the entire AP‐4 complex, leading to mislocalization of key cargo proteins—most notably ATG9A, a protein critical for autophagosome biogenesis—and consequent defects in autophagic flux. Studies in human patients have shown that loss‐of‐function mutations or deletions in AP4E1 are causative for a spectrum of neurodevelopmental disorders, including a subtype of hereditary spastic paraplegia (SPG51), cerebral palsy with intellectual disability, and associated features such as microcephaly and axonal swellings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In corresponding animal models, AP4E1 deficiency leads to neuroaxonal dystrophy, a thin corpus callosum, and impaired mobilization of ATG9A from the Golgi apparatus, supporting its essential role in maintaining neuronal homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, emerging evidence has linked heterozygous AP4E1 coding variants to persistent developmental stuttering, implicating deficits in intracellular trafficking as an underlying mechanism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Additional reports confirm that autosomal recessive mutations in AP4E1 result in SPG51, characterized by severe psychomotor retardation, spastic paraplegia, and supportive neuroimaging findings."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " The identification of similar clinical phenotypes across mutations in various AP‐4 subunits, including AP4E1, underscores the collective importance of AP‐4–mediated vesicular trafficking in neural development and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, genomic studies have nominated AP4E1 as a candidate gene within myeloid enhancer regions associated with Alzheimer’s disease risk, suggesting that perturbations in AP‐4–dependent sorting pathways may have broader implications in neurodegeneration"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and altered AP4E1 expression in lysosomal pathways hints at additional roles in intracellular trafficking beyond the nervous system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Collectively, these findings emphasize that AP4E1 is integral to intracellular protein trafficking, with its dysfunction contributing to a range of neurological disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andres Moreno-De-Luca, Sandra L Helmers, Hui Mao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2010.082263"}], "href": "https://doi.org/10.1136/jmg.2010.082263"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20972249"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20972249"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Darius Ebrahimi-Fakhari, Julian Teinert, Robert Behne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awz307"}], "href": "https://doi.org/10.1093/brain/awz307"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32979048"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32979048"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Rami Abou Jamra, Orianne Philippe, Annick Raas-Rothschild, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2011.04.019"}], "href": "https://doi.org/10.1016/j.ajhg.2011.04.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21620353"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21620353"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Raffaella De Pace, Miguel Skirzewski, Markus Damme, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1007363"}], "href": "https://doi.org/10.1371/journal.pgen.1007363"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29698489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29698489"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "M Hashim Raza, Rafael Mattera, Robert Morell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2015.10.007"}], "href": "https://doi.org/10.1016/j.ajhg.2015.10.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26544806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26544806"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Izabela Winkler, Paweł Miotła, Monika Lejman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new family with spastic paraplegia type 51 and novel mutations in AP4E1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Med Genomics (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12920-021-00980-5"}], "href": "https://doi.org/10.1186/s12920-021-00980-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34006278"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34006278"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hiroaki Murakami, Tomoko Uehara, Yoshinori Tsurusaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Blended phenotype of AP4E1 deficiency and Angelman syndrome caused by paternal isodisomy of chromosome 15."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Dev (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.braindev.2019.12.008"}], "href": "https://doi.org/10.1016/j.braindev.2019.12.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31955925"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31955925"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Beyhan Tüysüz, Kaya Bilguvar, Naci Koçer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.36514"}], "href": "https://doi.org/10.1002/ajmg.a.36514"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24700674"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24700674"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "G E Rudenskaya, D M Guseva, O L Mironovich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[AP4-assocated hereditary spastic paraplegias]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zh Nevrol Psikhiatr Im S S Korsakova (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.17116/jnevro202112102171"}], "href": "https://doi.org/10.17116/jnevro202112102171"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33728854"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33728854"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Gloriia Novikova, Manav Kapoor, Julia Tcw, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-21823-y"}], "href": "https://doi.org/10.1038/s41467-021-21823-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33712570"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33712570"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yanyan Li, Min Cheng, Yangfei Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effects of fluoride on PIWI-interacting RNA expression profiling in testis of mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chemosphere (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.chemosphere.2020.128727"}], "href": "https://doi.org/10.1016/j.chemosphere.2020.128727"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33213873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33213873"}]}]}]}
Synonyms	STUT1, CPSQ4, SPG51
Proteins	AP4E1_HUMAN
NCBI Gene ID	23431
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

AP4E1 has 5,928 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 115 datasets.

Click the + buttons to view associations for AP4E1 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

AP4E1 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of AP4E1 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of AP4E1 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of AP4E1 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of AP4E1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of AP4E1 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of AP4E1 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of AP4E1 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of AP4E1 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of AP4E1 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of AP4E1 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of AP4E1 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of AP4E1 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with AP4E1 protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of AP4E1 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of AP4E1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of AP4E1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with AP4E1 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of AP4E1 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing AP4E1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing AP4E1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing AP4E1 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing AP4E1 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with AP4E1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with AP4E1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing AP4E1 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with AP4E1 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with AP4E1 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with AP4E1 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of AP4E1 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by AP4E1 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving AP4E1 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with AP4E1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with AP4E1 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with AP4E1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with AP4E1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at AP4E1 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of AP4E1 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of AP4E1 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing AP4E1 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of AP4E1 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.