WFS1 Gene

Name	Wolfram syndrome 1 (wolframin)
Description	This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWFS1 encodes wolframin, an endoplasmic reticulum (ER)‐resident transmembrane glycoprotein predicted to have nine to ten membrane–spanning domains that is widely expressed (with particularly high levels in pancreatic β–cells and neural tissues). Under conditions of ER stress its expression is up–regulated, and its activity is essential for maintaining ER homeostasis and protecting cells from stress–induced apoptosis—a function that is critical for the survival of β–cells and other sensitive cell types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWolframin actively modulates the unfolded protein response by negatively regulating key ER stress pathways. In particular, it facilitates the proteasomal degradation of the transcription factor ATF6α, thereby suppressing the expression of stress–induced target genes and ensuring that ER stress signaling remains under tight control."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in regulating protein folding and stress responses, wolframin appears to contribute to intracellular ion homeostasis. Functional studies have demonstrated that wolframin can form a large cation–selective channel and is involved in modulating Ca²⁺ dynamics by enhancing the uptake of Ca²⁺ into the ER and regulating store–operated Ca²⁺ entry—mechanisms that are likely pivotal for proper insulin secretion and cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nProper function and stability of wolframin depend on its post–translational maturation, including essential N–glycosylation, which is required for its proper biogenesis and assembly into higher molecular weight complexes. Moreover, its interaction with other ER–resident proteins—such as the Na⁺/K⁺ ATPase β–subunit—underscores a role for wolframin in facilitating protein processing and maturation within the ER."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, the cellular levels of WFS1 are finely regulated via the ubiquitin–proteasome system. The E3 ubiquitin ligase Smurf1 targets wolframin for degradation under basal conditions—yet during ER stress, diminished Smurf1 activity leads to increased WFS1 levels. In parallel, wolframin interacts with the sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA), thereby influencing intracellular Ca²⁺ homeostasis through negative regulation of SERCA expression. This interconnected regulation highlights how WFS1 integrates protein processing and Ca²⁺ dynamics to help preserve cellular function under stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sonya G Fonseca, Mariko Fukuma, Kathryn L Lipson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M507426200"}], "href": "https://doi.org/10.1074/jbc.M507426200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16195229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16195229"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sonya G Fonseca, Shinsuke Ishigaki, Christine M Oslowski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI39678"}], "href": "https://doi.org/10.1172/JCI39678"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20160352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20160352"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Abdullah A Osman, Mitsuyoshi Saito, Carol Makepeace, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M310331200"}], "href": "https://doi.org/10.1074/jbc.M310331200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14527944"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14527944"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Daisuke Takei, Hisamitsu Ishihara, Suguru Yamaguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2006.09.007"}], "href": "https://doi.org/10.1016/j.febslet.2006.09.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16989814"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16989814"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sabine Hofmann, Christine Philbrook, Klaus-Dieter Gerbitz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddg214"}], "href": "https://doi.org/10.1093/hmg/ddg214"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12913071"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12913071"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Malgorzata Zatyka, Christopher Ricketts, Gabriela da Silva Xavier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddm296"}], "href": "https://doi.org/10.1093/hmg/ddm296"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17947299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17947299"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Xing Guo, Shan Shen, Shanshan Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ligase Smurf1 regulates Wolfram syndrome protein stability at the endoplasmic reticulum."}]}, {"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.M111.225615"}], "href": "https://doi.org/10.1074/jbc.M111.225615"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21454619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21454619"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Malgorzata Zatyka, Gabriela Da Silva Xavier, Elisa A Bellomo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu499"}], "href": "https://doi.org/10.1093/hmg/ddu499"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25274773"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25274773"}]}]}]}
Synonyms	WFS, WFRS, CTRCT41, WFSL
Proteins	WFS1_HUMAN
NCBI Gene ID	7466
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

WFS1 has 8,674 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 130 datasets.

Click the + buttons to view associations for WFS1 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

WFS1 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 WFS1 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 WFS1 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 WFS1 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 WFS1 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 WFS1 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 WFS1 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 WFS1 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 WFS1 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 WFS1 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 WFS1 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of WFS1 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 WFS1 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with WFS1 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with WFS1 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 WFS1 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of WFS1 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 WFS1 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with WFS1 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with WFS1 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 WFS1 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing WFS1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing WFS1 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with WFS1 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 WFS1 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of WFS1 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with WFS1 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with WFS1 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with WFS1 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with WFS1 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by WFS1 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving WFS1 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving WFS1 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with WFS1 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with WFS1 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 WFS1 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 WFS1 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 WFS1 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with WFS1 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 WFS1 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 WFS1 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.