MANF Gene

Name	mesencephalic astrocyte-derived neurotrophic factor
Description	The protein encoded by this gene is localized in the endoplasmic reticulum (ER) and golgi, and is also secreted. Reducing expression of this gene increases susceptibility to ER stress-induced death and results in cell proliferation. Activity of this protein is important in promoting the survival of dopaminergic neurons. The presence of polymorphisms in the N-terminal arginine-rich region, including a specific mutation that changes an ATG start codon to AGG, have been reported in a variety of solid tumors; however, these polymorphisms were later shown to exist in normal tissues and are thus no longer thought to be tumor-related. [provided by RefSeq, Apr 2014]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an evolutionarily conserved, endoplasmic reticulum (ER)–stress‐responsive protein that exerts dual intracellular and extracellular functions. In conditions of ER stress, MANF is upregulated and helps to restore proteostasis by modulating the unfolded protein response and repressing pro‐apoptotic signals, thereby promoting cell survival in neurons and pancreatic β‐cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n Its bifunctional structure—with a saposin‐like N‐terminal domain mediating neurotrophic activity and a C‐terminal region equipped with a crucial CXXC motif facilitating ER stress responses—underlies these protective effects."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In pancreatic islets, MANF supports β‐cell proliferation and survival, suggesting its potential as a therapeutic candidate in diabetes, while elevated serum MANF levels have been associated with clinical onset in children with type 1 diabetes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n In the nervous system, MANF protects dopaminergic neurons against diverse insults—including those mediated by misfolded proteins—and promotes repair following injuries such as those modeled in Parkinson’s disease and spinocerebellar ataxia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n Moreover, MANF exerts anti‐inflammatory actions by modulating NF‐κB and p38 MAPK signaling pathways, which contributes to tissue repair in the central nervous system, liver, and inner ear."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Tight regulation of MANF secretion and intracellular localization is achieved via its C‐terminal ER retention signal and interaction with chaperones such as GRP78, ensuring its proper deployment in response to stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings position MANF as a multifaceted cytoprotective and immunomodulatory mediator that facilitates ER homeostasis, supports neuronal and β‐cell survival, and modulates inflammatory responses—features that underscore its therapeutic promise in neurodegenerative diseases, metabolic disorders, and related conditions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "–."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andria Apostolou, Yuxian Shen, Yan Liang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2008.05.001"}], "href": "https://doi.org/10.1016/j.yexcr.2008.05.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18561914"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18561914"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Maria Lindahl, Tatiana Danilova, Erik Palm, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MANF is indispensable for the proliferation and survival of pancreatic β cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2014.03.023"}], "href": "https://doi.org/10.1016/j.celrep.2014.03.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24726366"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24726366"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Maarit Hellman, Urmas Arumäe, Li-ying Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.146738"}], "href": "https://doi.org/10.1074/jbc.M110.146738"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21047780"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21047780"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Vimal Parkash, Päivi Lindholm, Johan Peränen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Eng Des Sel (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/protein/gzn080"}], "href": "https://doi.org/10.1093/protein/gzn080"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19258449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19258449"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "K Mätlik, Li-ying Yu, A Eesmaa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of two sequence motifs of mesencephalic astrocyte-derived neurotrophic factor in its survival-promoting activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2015.371"}], "href": "https://doi.org/10.1038/cddis.2015.371"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26720341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26720341"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Emilia Galli, Taina Härkönen, Markus T Sainio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased circulating concentrations of mesencephalic astrocyte-derived neurotrophic factor in children with type 1 diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep29058"}], "href": "https://doi.org/10.1038/srep29058"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27356471"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27356471"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Su Yang, Shanshan Huang, Marta A Gaertig, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2013.12.002"}], "href": "https://doi.org/10.1016/j.neuron.2013.12.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24462098"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24462098"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kuan-Yin Tseng, Tatiana Danilova, Andrii Domanskyi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MANF Is Essential for Neurite Extension and Neuronal Migration in the Developing Cortex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "eNeuro (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/ENEURO.0214-17.2017"}], "href": "https://doi.org/10.1523/ENEURO.0214-17.2017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29082311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29082311"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jun Liu, Zhengsheng Wu, Dan Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mesencephalic Astrocyte-Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin-Related Modifier (SUMO)ylation-Related Suppression of NF-κB/Snail Signaling Pathway and Epithelial-Mesenchymal Transition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep.30917"}], "href": "https://doi.org/10.1002/hep.30917"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31469428"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31469428"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Pedro Sousa-Victor, Joana Neves, Wendy Cedron-Craft, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Metab (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s42255-018-0023-6"}], "href": "https://doi.org/10.1038/s42255-018-0023-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31489403"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31489403"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Wei Zhu, Jie Li, Yigang Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mesencephalic astrocyte-derived neurotrophic factor attenuates inflammatory responses in lipopolysaccharide-induced neural stem cells by regulating NF-κB and phosphorylation of p38-MAPKs pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunopharmacol Immunotoxicol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/08923973.2016.1168433"}], "href": "https://doi.org/10.3109/08923973.2016.1168433"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27075782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27075782"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Anni Herranen, Kuu Ikäheimo, Tuuli Lankinen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-020-2286-6"}], "href": "https://doi.org/10.1038/s41419-020-2286-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32029702"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32029702"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Kentaro Oh-Hashi, Kensuke Tanaka, Hisashi Koga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intracellular trafficking and secretion of mouse mesencephalic astrocyte-derived neurotrophic factor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-011-1155-0"}], "href": "https://doi.org/10.1007/s11010-011-1155-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22120531"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22120531"}]}]}]}
Synonyms	ARMET
Proteins	MANF_HUMAN
NCBI Gene ID	7873
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

MANF has 7,766 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 118 datasets.

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

If available, associations are ranked by standardized value

Harmonizome 3.0

MANF 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 MANF gene relative to other tissues from the Allen Brain Atlas Adult Human 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 MANF 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 MANF 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 MANF 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 MANF 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 MANF 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 MANF 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 MANF 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 MANF gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of MANF 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 MANF gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with MANF protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with MANF gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MANF gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of MANF 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 MANF gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of MANF gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing MANF protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of MANF gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing MANF protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing MANF protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing MANF 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 MANF 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 MANF 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 MANF protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with MANF gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with MANF gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with MANF gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of MANF 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 MANF gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving MANF gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with MANF gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with MANF 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 MANF 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 MANF gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with MANF 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 MANF 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 MANF gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of MANF 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 MANF from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.