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FNDC5 Gene

protein-coding   GIFtS: 48
GCID: GC01M033327

Fibronectin Type III Domain Containing 5

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(According to 1HGNC, 2Entrez Gene,
3UniProtKB/Swiss-Prot, 4UniProtKB/TrEMBL, 5OMIM, 6GeneLoc, 7Ensembl, 8DME, 9miRBase, 10fRNAdb, 12H-InvDB, 13NCBI, 14NONCODE, and/or 15RNAdb)
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Aliases
Fibronectin Type III Domain Containing 51 2
FRCP22 3 5
irisin1 2
Fibronectin Type III Repeat-Containing Protein 22 3
Fibronectin Type III Domain-Containing Protein 52

External Ids:    HGNC: 202401   Entrez Gene: 2529952   Ensembl: ENSG000001600977   OMIM: 6119065   UniProtKB: Q8NAU13   

Export aliases for FNDC5 gene to outside databases

Previous GC identifers: GC01M032830 GC01M032996 GC01M033100 GC01M031443


(According to Entrez Gene, GeneCards, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
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Entrez Gene summary for FNDC5 Gene:
This gene encodes a secreted protein that is released from muscle cells during exercise. The encoded protein may
participate in the development of brown fat. Translation of the precursor protein initiates at a non-AUG start
codon at a position that is conserved as an AUG start codon in other organisms. Alternative splicing results in
multiple transcript variants. (provided by RefSeq, Jun 2013)

GeneCards Summary for FNDC5 Gene:
FNDC5 (fibronectin type III domain containing 5) is a protein-coding gene. GO annotations related to this gene include hormone activity. An important paralog of this gene is FNDC4.

UniProtKB/Swiss-Prot: FNDC5_HUMAN, Q8NAU1
Function: Irisin: Contrary to mouse, may not be involved in the beneficial effects of muscular exercise, nor in
the induction of browning of human white adipose tissue (PubMed:24040023)




(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 75), Regulatory elements and Epigenetics data according to QIAGEN, and/or SwitchGear Genomics)
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RefSeq DNA sequence at NCBI GenBank:
NC_000001.10  NC_018912.2  NT_032977.10  
Regulatory elements:
   Regulatory transcription factor binding sites in the FNDC5 gene promoter:
         Nkx3-1   CREB   deltaCREB   NRSF form 1   Nkx3-1 v1   NRSF form 2   GATA-2   
         Other transcription factors

SwitchGear Promoter luciferase reporter plasmidFNDC5 promoter sequence
   Search Chromatin IP Primers for FNDC5

Epigenetics:
DNA Methylation CpG Assay Predesigned for Pyrosequencing in human, mouse, rat FNDC5


Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 1p35.1   Ensembl cytogenetic band:  1p35.1   HGNC cytogenetic band: 1p34.3

FNDC5 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
FNDC5 gene location

GeneLoc information about chromosome 1         GeneLoc Exon Structure

GeneLoc location for GC01M033327:  view genomic region     (about GC identifiers)

Start:
33,327,869 bp from pter      End:
33,338,083 bp from pter
Size:
10,215 bases      Orientation:
minus strand

(According to 1UniProtKB, HORDE, 2neXtProt, Ensembl, and/or Reactome, Modification sites according to PhosphoSitePlus, Specific Peptides from DME, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, Cloud-Clone Corp., and/or eBioscience,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, Cloud-Clone Corp., and/or eBioscience, Antibodies by EMD Millipore, R&D Systems, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, LSBio, Abcam, Cloud-Clone Corp, and/or others.)
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UniProtKB/Swiss-Prot: FNDC5_HUMAN, Q8NAU1 (See protein sequence)
Recommended Name: Fibronectin type III domain-containing protein 5 precursor  
Size: 212 amino acids; 23659 Da
Caution: It is uncertain whether Met-1 or Met-76 is the initiator. Transcript evidence available at present time
points at Met-76. In this short version of the protein, the signal peptide cannot be predicted and the irisin
peptide is severely truncated. The first initiation codon corresponds to a non-AUG site, an N-terminal ATA codon.
This initiation codon has been annotated as it is in good Kozak context and it is conserved in other primates,
including gibbon, chimpanzee and gorilla. Although the existence of such a form has not been demonstrated in
human, western blot analysis following endurance exercise shows the presence of an irisin peptide of similar size
in human and mouse plasma (PubMed:22237023), suggesting the existence of full length irisin in human, at least in
some tissues. However, expression from Met-1 may be less efficient than that from Met-76 (PubMed:24040023)
1 PDB 3D structure from and Proteopedia for FNDC5:
4LSD (3D)    
Secondary accessions: A6NMC9 D3DPQ6 Q6P6D9 Q7Z676
Alternative splicing: 4 isoforms:  Q8NAU1-1   Q8NAU1-2   Q8NAU1-3   Q8NAU1-4   (No experimental confirmation available)

Explore the universe of human proteins at neXtProt for FNDC5: NX_Q8NAU1

Explore proteomics data for FNDC5 at MOPED

Post-translational modifications: 

  • The extracellular domain is cleaved and released from the cell membrane1
  • N-Glycosylated (By similarity)1
  • Glycosylation2 at Asn39, Asn84
  • Modification sites at PhosphoSitePlus

  • See FNDC5 Protein Expression from SPIRE MOPED, PaxDB, and MaxQB

    REFSEQ proteins (3 alternative transcripts): 
    NP_001165411.2  NP_001165412.1  NP_715637.2  

    ENSEMBL proteins: 
     ENSP00000362570   ENSP00000476320   ENSP00000476668  

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    (According to HGNC, IUPHAR, InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
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    HGNC Gene Families:
    FN3: Fibronectin type III domain containing

    2 InterPro protein domains:
     IPR003961 Fibronectin_type3
     IPR013783 Ig-like_fold

    Graphical View of Domain Structure for InterPro Entry Q8NAU1

    ProtoNet protein and cluster: Q8NAU1

    UniProtKB/Swiss-Prot: FNDC5_HUMAN, Q8NAU1
    Similarity: Contains 1 fibronectin type-III domain


    Find genes that share domains with FNDC5           About GenesLikeMe


    (According to 1UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or 2DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013, inGenious Targeting Laboratory, genOway,
    transcription factor targeting from QIAGEN and/or HOMER, miRNA Gene Targets from miRTarBase, shRNA from OriGene, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, SwitchGear Genomics, Gene Editing from DNA2.0, Clones from OriGene, GenScript, Sino Biological, DNA2.0, Vector BioLabs and/or Addgene, Cell Lines from GenScript, ESI BIO, In Situ Hybridization Assays from Advanced Cell Diagnostics, Flow cytometry from eBioscience, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Molecular Function:

         UniProtKB/Swiss-Prot Summary: FNDC5_HUMAN, Q8NAU1
    Function: Irisin: Contrary to mouse, may not be involved in the beneficial effects of muscular exercise, nor in
    the induction of browning of human white adipose tissue (PubMed:24040023)
    Induction: Has been shown to be up-regulated some twofold by muscular exercise at the mRNA and protein level; this
    effect has been suggested to be mediated by PPARGC1A (PubMed:22237023). However, up-regulation upon exercise
    could not be reproduced, at least not at the mRNA level (PubMed:24040023)

         Gene Ontology (GO): 3 molecular function terms:    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0003674molecular_function ND--
    GO:0005179hormone activity IEA--
    GO:0005515protein binding ----
         
    Find genes that share ontologies with FNDC5           About GenesLikeMe


    Phenotypes:
         1 GenomeRNAi human phenotype for FNDC5:
     Increased S DNA content 

    Animal Models:
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    (According to UniProtKB, COMPARTMENTS Subcellular localization database, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Subcellular locations from UniProtKB/Swiss-Prot
    FNDC5_HUMAN, Q8NAU1: Cell membrane; Single-pass type I membrane protein. Peroxisome membrane; Single-pass type I
    membrane protein (By similarity). Note=Imported in peroxisomes through the PEX5 receptor pathway (By similarity)
    FNDC5_HUMAN, Q8NAU1: Irisin: Secreted. Note=Detected in the blood of individuals subjected to endurance exercise
    (PubMed:22237023)
    Subcellular locations from COMPARTMENTS: 

    CompartmentConfidence
    extracellular5
    peroxisome5
    plasma membrane5
    endoplasmic reticulum4
    cytosol1
    mitochondrion1

    Gene Ontology (GO): 5 cellular component terms:    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0005576extracellular region ISS--
    GO:0005778peroxisomal membrane IEA--
    GO:0005783endoplasmic reticulum ISS--
    GO:0005886plasma membrane ISS--
    GO:0016021integral component of membrane IEA--

    Find genes that share ontologies with FNDC5           About GenesLikeMe


    (SuperPaths according to PathCards, Pathways according to R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Sino Biological, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to QIAGEN, and/or STRING, Interactions according to 1UniProtKB, 2MINT, 3I2D, and/or 4STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene).
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        Custom Pathway & Disease-focused RT2 Profiler PCR Arrays for FNDC5
    Interactions:

        Search GeneGlobe Interaction Network for FNDC5

    STRING Interaction Network Preview (showing 4 interactants - click image to see more details)

    4 Interacting proteins for FNDC5 (Q8NAU13 ENSP000003625704) via UniProtKB, MINT, STRING, and/or I2D
    InteractantInteraction Details
    GeneCardExternal ID(s)
    PTSQ033933, ENSP000002803624I2D: score=4 STRING: ENSP00000280362
    C1orf105ENSP000003567004STRING: ENSP00000356700
    CRYZENSP000003393994STRING: ENSP00000339399
    ENSG00000228284ENSP000004143604STRING: ENSP00000414360
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    Gene Ontology (GO): 3 biological process terms:    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0008150biological_process ND--
    GO:0014850response to muscle activity ISS--
    GO:0090336positive regulation of brown fat cell differentiation ISS--

    Find genes that share ontologies with FNDC5           About GenesLikeMe



    (Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience, ApexBio, HMDB, BitterDB, and/or Novoseek, Ligands according to IUPHAR, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB)
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    Browse Small Molecules at EMD Millipore
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    Browse Tocris compounds for FNDC5



    (Secondary structures according to fRNAdb,
    GenBank/EMBL/DDBJ Accessions according to
    Unigene (Build 236 Homo sapiens; Apr 25 2013) or GenBank,
    RefSeq according to Entrez Gene,
    DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
    exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
    siRNAs from OriGene, QIAGEN, shRNA from OriGene, microRNA from QIAGEN, SwitchGear Genomics,
    Tagged/untagged cDNA clones from OriGene, GenScript, DNA2.0, Vector BioLabs, and/or Addgene, Primers from OriGene, and/or QIAGEN, Flow cytometry from eBioscience )
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    REFSEQ mRNAs for FNDC5 gene (3 alternative transcripts): 
    NM_001171940.1  NM_001171941.2  NM_153756.2  

    Unigene Cluster for FNDC5:

    Fibronectin type III domain containing 5
    Hs.524234  [show with all ESTs]
    Unigene Representative Sequence: NM_001171941
    7 Ensembl transcripts including schematic representations, and UCSC links where relevant:
    ENST00000483143 ENST00000481487 ENST00000373471(uc001bwe.3 uc021okv.1 uc001bwf.2 uc001bwg.3)
    ENST00000497068 ENST00000496770 ENST00000465346 ENST00000609187
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    Additional mRNA sequence: 

    AK092102.1 BC007548.1 BC033123.1 BC062297.1 BX537781.1 

    5 DOTS entries:

    DT.106354  DT.75152000  DT.100752500  DT.100752501  DT.92420744 

    Selected AceView cDNA sequences (see all 135):

    BF445493 BM714183 BE467868 AW054777 BC007548 AK092102 BE549729 AI701106 
    BE673945 AI680619 BE551417 AA570017 BE218308 BI757899 AX747354 AI391724 
    T16538 BC033123 AI694150 NM_153756 BF221649 BE467031 AI468318 BF447318 

    GeneLoc Exon Structure

    4 Alternative Splicing Database (ASD) splice patterns (SP) for FNDC5    About this scheme

    ExUns: 1 ^ 2a · 2b ^ 3 ^ 4 ^ 5 ^ 6a · 6b · 6c ^ 7a · 7b · 7c
    SP1:                                                  -                     
    SP2:                                            -     -     -     -         
    SP3:        -     -                                                         
    SP4:                                                  -     -               


    ECgene alternative splicing isoforms for FNDC5

    (RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, Protein expression images according to data from SPIRE 1MOPED, 2PaxDb, and 3MaxQB, plus additional links to SOURCE, and/or BioGPS, and/or UniProtKB,
    PCR Arrays from QIAGEN, Primers from OriGene, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
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    FNDC5 expression in normal human tissues (normalized intensities)
    See probesets specificity/sensitivity at GeneAnnot
    About this imageBioGPS <intensity>2/3
    CGAP TAG: AGGCTCCACT
    FNDC5 Expression
    About this image


    FNDC5 expression in embryonic tissues and stem cells    About this table
    Data from LifeMap, the Embryonic Development and Stem Cells Database
     selected tissues (see all 2) fully expand
     
     Ovary (Reproductive System)    fully expand to see all 2 entries
             Pre-Granulosa Cells Primordial Follicle
     
     Head Mesenchyme (Muscoskeletal System)
             Head Mesenchyme
    FNDC5 Protein expression data from MOPED1, PaxDb2 and MaxQB3    About this image

    FNDC5 Protein Expression

    SOURCE GeneReport for Unigene cluster: Hs.524234

    UniProtKB/Swiss-Prot: FNDC5_HUMAN, Q8NAU1
    Tissue specificity: Widely expressed, with highest levels in heart. Very low expression, if any, in colon,
    pancreas and spleen

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    (Orthologs according to 1,2HomoloGene (2older version, for species not in 1newer version), 3euGenes, 4SGD , 5MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or 6Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
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    This gene was present in the common ancestor of chordates.

    Orthologs for FNDC5 gene from Selected species (see all 10)    About this table
    Organism Taxonomic
    classification
    Gene Description Human
    Similarity
    Orthology
    Type
    Details
    mouse
    (Mus musculus)
    Mammalia Fndc51 , 5 fibronectin type III domain containing 51, 5 90.59(n)1
    98.56(a)1
      4 (62.93 cM)5
    3840611  NM_027402.31  NP_081678.11 
     1291369995 
    chicken
    (Gallus gallus)
    Aves FNDC51 fibronectin type III domain containing 5 82.17(n)
    91.98(a)
      419667  XM_417814.4  XP_417814.4 
    lizard
    (Anolis carolinensis)
    Reptilia FNDC56
    fibronectin type III domain containing 5
    30(a)
    1 ↔ 1
    GL343711.1(154096-160077)
    zebrafish
    (Danio rerio)
    Actinopterygii fndc5a1 fibronectin type III domain containing 5a 71.82(n)
    74.23(a)
      795265  XM_001335368.2  XP_001335404.2 


    ENSEMBL Gene Tree for FNDC5 (if available)
    TreeFam Gene Tree for FNDC5 (if available)

    (Paralogs according to 1HomoloGene,
    2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
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    Paralogs for FNDC5 gene
    FNDC42  
    1 SIMAP similar gene for FNDC5 using alignment to 1 protein entry:     FNDC5_HUMAN:
    FNDC4

    Find genes that share paralogs with FNDC5           About GenesLikeMe



    (SNPs/Variants according to the 1NCBI SNP Database, 2Ensembl, 3PupaSUITE, 4UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD), the Human Cytochrome P450 Allele Nomenclature Database, and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers, Cancer Mutation PCR Arrays and Assays, and Copy Number PCR Arrays from QIAGEN)
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    Selected SNPs for FNDC5 (see all 465)    About this table                                 

    Genomic DataTranscription Related DataAllele Frequencies
    SNP IDValidClinical
    significance
    Chr 1 posSequence#AA
    Chg
    TypeMore#Allele
    freq
    PopTotal
    sample
    More
    ----------
    rs1856584791,2
    --31452068(+) TGCCCA/GTTTGT 1 -- int10--------
    rs1900796121,2
    --31452236(+) GTGTTG/TCCAGT 1 -- int10--------
    rs1823199391,2
    --31452256(+) AAGAGG/TCTGCT 1 -- int10--------
    rs1875356841,2
    --31452277(+) GGAGAA/GTCCAG 1 -- int10--------
    rs1909282431,2
    --31452598(+) GTGAGA/TCTCTA 1 -- int10--------
    rs107989191,2
    C,F,A,H--31452631(+) CCCCAA/GCCAGA 1 -- int111Minor allele frequency- G:0.41NA WA CSA EA 374
    rs120860091,2
    C,F--31452646(+) AGTCTG/ACAGCA 1 -- int12Minor allele frequency- A:0.15WA 120
    rs1888859551,2
    --31453569(+) TCCCTA/GCAGGG 1 -- int10--------
    rs1845117791,2
    --31453758(+) TTGGAA/GGATTT 1 -- int10--------
    rs107532681,2
    C,F,A,H--31453837(+) TCTGGT/GGAAAG 1 -- int1 tfbs310Minor allele frequency- G:0.33NA WA CSA EA 371

    HapMap Linkage Disequilibrium report for FNDC5 (33327869 - 33338083 bp)

    Structural Variations
         Database of Genomic Variants (DGV) 1 variation for FNDC5:    About this table    
    Variant IDTypeSubtypePubMed ID
    nsv516302CNV Loss19592680

    Site Specific Mutation Identification with PCR Assays
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    (in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
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    OMIM gene information: 611906    OMIM disorders: --


    Find genes that share disorders with FNDC5           About GenesLikeMe


    Export disorders for FNDC5 gene to outside databases

    (in PubMed. Associations of this gene to articles via 1Entrez Gene, 2UniProtKB/Swiss-Prot, 3HGNC, 4GAD, 5PharmGKB, 6HMDB, 7DrugBank, 8UniProtKB/TrEMBL, 9 Novoseek, and/or 10fRNAdb)
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    PubMed articles for FNDC5 gene, integrated from 10 sources (see all 28):
    (articles sorted by number of sources associating them with FNDC5)
        Utopia: connect your pdf to the dynamic
    world of online information

    1. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. (PubMed id 22237023)1, 2, 3 Bostrom P....Spiegelman B.M. (Nature 2012)
    2. Exercise induces hippocampal BDNF through a PGC-1I+/FNDC5 pathway. (PubMed id 24120943)1, 3 Wrann C.D....Spiegelman B.M. (Cell Metab. 2013)
    3. Complete sequencing and characterization of 21,243 full-length human cDNAs. (PubMed id 14702039)1, 2 Ota T.... Sugano S. (Nat. Genet. 2004)
    4. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. (PubMed id 12384288)1, 3 Teufel A....Westphal H. (Gene 2002)
    5. Irisin ERKs the fat. (PubMed id 24464712)1 Wu J. and Spiegelman B.M. (Diabetes 2014)
    6. Irisin in patients with nonalcoholic fatty liver disease. (PubMed id 24140091)1 Polyzos S.A....Mantzoros C.S. (Metab. Clin. Exp. 2014)
    7. The structure of irisin reveals a novel intersubunit I^-sheet fibronectin type III (FNIII) dimer: implications for receptor activation. (PubMed id 24114836)1 Schumacher M.A....Erickson H.P. (J. Biol. Chem. 2013)
    8. Decrease in irisin in patients with chronic kidney disease. (PubMed id 23667695)1 Wen M.S....Hung K.C. (PLoS ONE 2013)
    9. Evidence against a Beneficial Effect of Irisin in Humans. (PubMed id 24040023)2 Raschke S.... Eckel J. (PLoS ONE 2013)
    10. Serum irisin levels in new-onset type 2 diabetes. (PubMed id 23369227)1 Choi Y.K....Park K.G. (Diabetes Res. Clin. Pract. 2013)

    (in PubMed, OMIM, and NCBI Bookshelf)
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     ANDOR
    Aliases
    Free Text  

      Query String
    PubMed
    OMIM
    NCBI Bookshelf
      (Note: In FireFox, select the above section and copy using Ctrl-C)

    (According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
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    Entrez Gene: 252995 HGNC: 20240 AceView: FNDC5 Ensembl:ENSG00000160097 euGenes: HUgn252995
    ECgene: FNDC5 H-InvDB: FNDC5

    (According to HUGE)
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      --

    (According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, UniProtKB/TrEMBL, and/or others, e.g. Wikipedia and GeneReviews, via UniProtKB/Swiss-Prot)
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    NameDescription
    PharmGKB entry for FNDC5 Pharmacogenomics, SNPs, Pathways

    (Patent information from GeneIP,
    Licensable technologies from WIS Yeda, Salk, Tufts,
    IP news from LifeMap Sciences, Inc.)
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    Patent Information for FNDC5 gene:
    Search GeneIP for patents involving FNDC5

    GeneCards and IP:
    Japan Patent Office Licenses GeneCards     European Patent Office Licenses GeneCards     Improving the IP Search



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