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FLASH GENE
Symbol WFS1 contributors: mct - updated : 31-08-2011
HGNC name Wolfram syndrome 1 (wolframin)
HGNC id 12762
Corresponding disease
DFNA14 neurosensory deafness 14
DFNA38 neurosensory deafness 38
DFNA6 neurosensory deafness 6
DIDMOAD Wolfram syndrome
JOD juvenile-onset diabetes
Location 4p16.1      Physical location : 6.271.576 - 6.304.991
Synonym name wolframin
Synonym symbol(s) WM1, WFRS, WFS, FLJ51211
DNA
TYPE functioning gene
STRUCTURE 33.42 kb     8 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter (CAAT box)
Binding site   transcription factor
text structure
  • a conserved sequence (CGAGGCGCACCGTGATTGG) that is highly similar to the ER stress response element (ERSE), critical for the regulation of WFS1 by XBP1
  • minimal promoter contains two DNA binding motifs (GC boxes) for the transcription factors Sp1/3/4 (transcription factors of the Sp family are important regulators of the WFS1 promoter)
  • up-regulating control region containing three CCAAT box binding motifs
  • MAPPING cloned Y linked N status confirmed
    Physical map
    MGC13159 4p16.2 hypothetical protein MGC13159 LYAR 4p16.2 hypothetical protein FLJ20425 ZNF509 4p16.2 zinc finger protein 509 D4S234E 4p16.3 DNA segment on chromosome 4 (unique) 234 expressed sequence STX18 4p16.2 syntaxin 18 MSX1 4p16.3-p16.1 msh homeo box homolog 1 (Drosophila) LDHAL1 4p16.3-p15.3 lactate dehydrogenase A-like 1 LOC132870 4p16.2 hypothetical gene LOC132870 C17 4p16-p15 hypothetical gene LOC132870 HSA250839 4p16.2 gene for serine/threonine protein kinase C4orf6 4p16 chromosome 4 open reading frame 6 EVC2 4p16.2-p16.1 Ellis van Creveld syndrome 2 (limbin) EVC 4p16 Ellis van Creveld syndrome CRMP1 4p16.1-p15 collapsin response mediator protein 1 LOC389197 4 hypothetical gene supported by BX648674 FLJ31564 LOC389198 4 LOC389198 WFS1 4p16.1 Wolfram syndrome 1 (wolframin) PPP2R2C 4p16.1 protein phosphatase 2 (formerly 2A), regulatory subunit B (PR 52), gamma isoform KIAA0935 4p16.1 protein phosphatase 2 (formerly 2A), regulatory subunit B (PR 52), gamma isoform PGR1 4p16.1 T-cell activation protein LOC93622 4p16.1 hypothetical protein BC006130 S100P 4p16 S100 calcium binding protein P MGC9651 4p16.1 hypothetical protein MGC9651 CNO 4p16.1 cappuccino KIAA0232 4p16.1 KIAA0232 gene product KIAA1322 FLJ90575 4p16.1 hypothetical protein FLJ90575 MGC21874 4p16.1 transcriptional adaptor 2 (ADA2 homolog, yeast)-beta GRPEL1 4p16 GrpE-like 1, mitochondrial (E. coli) SORCS2 4p16 GrpE-like 1, mitochondrial (E. coli) AFAP 4p16 actin filament associated protein MGC10981 4p16.1 hypothetical protein MGC10981 LOC389199 4 hypothetical gene supported by BC031673 ABLIM2 4p16-p15 actin binding LIM protein 2
    RNA
    TRANSCRIPTS type messenger
    text variants 1 and 2 encode the same protein
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 3640 - 890 - 2011 21454619
    8 - 3636 - 890 - 2011 21454619
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrinepancreas     Homo sapiens
    Nervousbrainhindbraincerebellum   Mus musculus
     brainlimbic systemhippocampusAmmons horn  Mus musculus
     braindiencephalonamygdala   Mus musculus
    Olfactory (smell)olfactory bulb     Mus musculus
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Endocrineislet cell (alpha,beta...) Homo sapiens
    Nervousneuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta
    IMPRINTING
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N and C terminal hydrophilic regions
  • N-terminal cytoplasmic domain (AAs 2-285) binds to an equimolar unit of CALM1 in a Ca(2+)-dependent manner , and N-terminal domain is located in the cytoplasm, interacting with ATP6V1A
  • a central hydrophobic core
  • nine transmembrane domains
  • five putative ASN glycosylation sites
  • a sequence homolog to the prenyltransferase alpha subunit repeat structure
  • C-terminal domain of the WFS1 protein is located in the ER lumen
  • secondary structure endoglycosidase H sensitive
    conjugated GlycoP
    HOMOLOGY
    interspecies homolog to murine Wfs1 (87.60 pc)
    homolog to rattus Wfs1 (86.92 pc)
    Homologene
    FAMILY
  • multispanning transmembrane family
  • CATEGORY regulatory , storage , transport
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic,granule
    intracellular,nucleus
    text
  • endoplasmic reticulum (ER) resident transmembrane protein
  • additionally located in the secretory granules of pancreatic beta cells
  • basic FUNCTION
  • playing a role in survival of islet beta-cells and neurons
  • may be playing a role in membrane trafficking, protein processing, or regulation of ER calcium homeostasis
  • playing an important role in both stimulus-secretion coupling for insulin exocytosis and maintenance of the beta-cell mass
  • playing a regulatory rolesin ER-stress induced cell death
  • having an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic beta-cells
  • negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6), through the ubiquitin-proteasome pathway
  • role in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic beta cell death in diabetes
  • plays a key role in the negative regulation of a feedback loop of the ER stress network through the ubiquitin proteasome pathway
  • localizes to secretory granules and determines granule acidification in pancreatic beta-cells
  • endoplasmic reticulum (ER)-resident transmembrane protein that also localizes to secretory granules in pancreatic beta cells
  • is involved in the stability of proton and sodium pump subunits, but does not protect ATP6V1A and ATP1B1 from proteasome-mediated degradation
  • is thought to be a negative regulator of the ER stress response
  • is necessary for the stability of the ATP6V1A subunit independently of its role in ER stress
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS cellular trafficking transport
    text
  • membrane trafficking
  • PATHWAY
    metabolism carbohydrate
    signaling sensory transduction/hearing , sensory transduction/vision
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with CALM1 (CALM1 binding is important for wolframin function and impairment of this interaction by mutation contributes to the pathology seen in Wolfram syndrome)
  • specific degradation substrate of SMURF1 (interacts with WFS1 at the ER and promotes the ubiquitination and proteasomal degradation of WFS1)
  • interaction between WFS1 and ATP6V1A (proton pump)
  • cell & other
    REGULATION
    activated by during insulin secretion
    XBP1
    induced by ER stress
    Other regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response
    ASSOCIATED DISORDERS
    corresponding disease(s) DIDMOAD , DFNA6 , DFNA14 , DFNA38 , JOD
    related resource Hereditary Hearing Loss Homepage
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional somatic mutation     loss of function
    leading to instability and proteasomal degradation of wolframin
    Susceptibility to common type 2 diabetes
    Variant & Polymorphism SNP increasing the risk of type 2 diabetes
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Wfs1-null mouse exhibits progressive insulin deficiency causing diabetes
  • mice with disrupted WFS1 exhibit progressive pancreatic beta cell loss, resulting from the activation of ER stress pathways, delayed cell cycle progression and apoptosis