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FLASH GENE
Symbol GRN contributors: mct - updated : 27-02-2015
HGNC name granulin
HGNC id 4601
Corresponding disease
CLN11 ceroid lipofuscinosis, neuronal, 11
FTDU17 familial frontotemporal dementia, tau-negative
Location 17q21.31      Physical location : 42.422.490 - 42.430.470
Synonym name
  • PC cell-derived growth factor
  • acrogranin
  • granulin-epithelin precursor
  • proepithelin
  • progranulin
  • Synonym symbol(s) GRA, GEP, GP88, PEPI, PGRN, PCDGF, CLN11
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head
    STRUCTURE 7.98 kb     13 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Physical map
    RNU2P2 17q21.31 RNA, U2 small nuclear pseudogene 2 ARF4L 17q12-q21 ADP-ribosylation factor 4-like LOC284064 17q21.31 similar to 60S ribosomal protein L29 (Cell surface heparin binding protein HIP) DHX8 17q21.31 DEAH (Asp-Glu-Ala-His) box polypeptide 8 ETV4 17q21 ets variant gene 4 (E1A enhancer binding protein, E1AF) MEOX1 17q21 mesenchyme homeo box 1 LOC390797 17 similar to WHSC1L1 protein isoform long; Wolf-Hirschhorn syndrome candidate 1-like 1 protein SOST 17q12-q21 sclerosteosis DUSP3 17q21 dual specificity phosphatase 3 (vaccinia virus phosphatase VH1-related) LOC284067 17q21.31 hypothetical LOC284067 MPP3 17q12-q21 membrane protein, palmitoylated 3 (MAGUK p55 subfamily member 3) TREM4 17q21.31 triggering receptor expressed on myeloid cells 4 MPP2 17q12-q21 membrane protein, palmitoylated 2 (MAGUK p55 subfamily member 2) APR-2 17q21.31 apoptosis related protein LOC390798 17 similar to wingless-type MMTV integration site family, member 9B precursor; wingless-type MMTV integration site family, member 15 PPY 17q21.2 pancreatic polypeptide PYY 17q21.1 peptide YY NAGS 17q21.31 peptide YY MGC4251 17q21.31 hypothetical protein MGC4251 FLJ30656 17q21.31 hypothetical protein FLJ30656 G6PC3 17q21.31 glucose-6-phosphatase catalytic subunit 3 HDAC5 17q21 histone deacetylase 5 MGC3130 17q21.31 hypothetical protein MGC3130 ASB16 17q21.31 ankyrin repeat and SOCS box-containing 16 DKFZp762C2414 17q21.31 hypothetical protein DKFZp762C2414 MGC3123 17q21.31 hypothetical protein MGC3123 UBTF 17q21.3 upstream binding transcription factor, RNA polymerase I LOC390799 17 similar to SHC (Src homology 2 domain containing) transforming protein 1; SHC (Src homology 2 domain-containing) transforming protein 1 SLC4A1 17q21-q22 solute carrier family 4, anion exchanger, member 1 (erythrocyte membrane protein band 3, Diego blood group) RPIP8 17p13.2 solute carrier family 4, anion exchanger, member 1 (erythrocyte membrane protein band 3, Diego blood group) CGI-69 17q12 CGI-69 protein GRN 17q21.3 granulin MGC34829 17q21.31 Similar to hypothetical gene supported by AL050367; AK022946 LOC390800 17 similar to ribosomal protein L7-like 1 ITGA2B 17q21.32 integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B) KIAA0553 17q21.31 KIAA0553 protein FZD2 17q21.1 frizzled homolog 2 (Drosophila) FLJ35848 17q21.31 hypothetical protein FLJ35848 FLJ31795 17q21.31 hypothetical protein FLJ31795 DRF1 17q21.31 Dbf4-related factor 1 ADAM11 17q21.3 a disintegrin and metalloproteinase domain 11 GJA7 17q21.31 gap junction protein, alpha 7, 45kDa (connexin 45) CLST11240 17q21.31 CLST 11240 protein U5-116KD 17q21.31 U5 snRNP-specific protein, 116 kD LOC388389 17 similar to RIKEN cDNA 4933439F11 GFAP 17q21.1 glial fibrillary acidic protein LOC146909 17q21.31 hypothetical protein LOC146909 CRF 17q21 C1q-related factor FLJ22955 17q21.31 hypothetical protein FLJ22955 NMT1 17q21.32 N-myristoyltransferase 1 PLCD3 17q21 phospholipase C, delta 3 ACBD4 17q21.31 acyl-Coenzyme A binding domain containing 4
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    13 splicing 2323 63.5 593 - 1993 8471244
    a 576 aa mature peptide (61.8 kda)
    - splicing 1858 - 438 - 2006 16862116
  • 12 exons
  • lacking an exon compared to variant 1
  • using multiple, alternate, in-frame splice sites in the 3' coding region compared to variant 1
  • a 421 aa mature peptide (45.2 kda)
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
     liver     Homo sapiensFetal
    Lymphoid/Immunespleen   highly
     thymus   highly
    Nervousbrainforebraincerebral cortex   Homo sapiens
     spinal cordanterior horn    Homo sapiensAdult
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose    Mus musculusAdult
    Muscularstriatumskeletal   Homo sapiensAdult
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveodontoblast Homo sapiensAdult
    Nervousglia Homo sapiensAdult
    Nervousneuron Homo sapiens
    NervousPurkinje cell Homo sapiens
    Nervouspyramidal cell Homo sapiens
    not specificadipocyte Mus musculusAdult
    cell lineage
    cell lines
    fluid/secretion moderately in blood
    at STAGE
    Text liver
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • seven and a half granulin domains composed of 12 cysteine-rich tandem repeat motifs
  • conjugated GlycoP
    isoforms Precursor a 17 aa signal peptide (1.8kda), smaller cleavage products named granulin A, granulin B, granulin C, etc.
    HOMOLOGY
    interspecies homolog to rattus Grn (76pc)
    homolog to murine Grn (75.7pc)
    Homologene
    FAMILY
  • granulin family
  • CATEGORY immunity/defense , transcription factor , protooncogene , signaling cytokine
    SUBCELLULAR LOCALIZATION extracellular
    intracellular,cytoplasm,organelle,mitochondria
    text in pachytene spermatocytes and is found later in the acrosomes of developing spermatids and sperm
    basic FUNCTION
  • having growth modulatory activity
  • having possible cytokine-like activity
  • may play a role in inflammation, wound repair,
  • and tissue remodeling (being a crucial mediator of wound response and tissue repair)
  • involved in the stimulation of chondrocyte proliferation (stimulation mediated by COMP)
  • may act as a wound-healing factor, although the granulins and the full-length PGRN may have opposite functions in wound repair and inflammation
  • germ cell-specific glycoprotein that was expressed meiotically and post-meiotically, having growth-modulating properties
  • importance of progranulin as neuroprotective growth factor
  • important role in tooth formation during postnatal development
  • function for progranulin in modulating the kinetics of programmed cell death that may be relevant for neuron loss in neurodegenerative diseases
  • neurotrophic factor that enhances neuronal survival and axonal growth
  • GRN growth factor, JUNB, and MYOD1 transcription factor form a regulatory loop and act in concert in the course of myogenesis
  • hepatic oncofetal protein regulating ES cell-related signaling molecules
  • key adipokine that mediates HFD (high fat diet)-induced insulin resistance and obesity through production of IL6 in adipose tissue
  • microglial PGRN appears to function as an endogenous modulator of innate immune responses
  • widely expressed secreted protein that is linked to inflammation
  • critical role of GRN in lysosomes
  • is likely essential for proper lysosomal function
  • CELLULAR PROCESS cell life, proliferation/growth
    nucleotide, transcription
    PHYSIOLOGICAL PROCESS inflammation , nervous system , reproduction/sex
    text epithelial homeostasis, reproductive, immunological, neuronal function
    PATHWAY
    metabolism
    signaling signal transduction
    cell-cell signaling; positive regulation of cell proliferation
    a component
  • disulfide bridged
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • selectively interacts with the epidermal growth factor repeat domain of COMP but not with the other three functional domains of COMP
  • interacting with TARDBP (may be required as a survival factor for vulnerable neurons, which accumulate cytoplasmic TARDBP fragments because of other reasons)
  • important role of PGRN in neurite outgrowth and involvement of GSK3B in mediating PGRN activity
  • substrate of several protein disulfide isomerase family proteins
  • adipokine induced by TNF and dexamethasone
  • MMP12 is a PGRN proteolytic enzyme, and SLPI an inhibitor of MMP12-induced PGRN proteolysis
  • overexpression of TMEM106B correlates with elevated levels of GRN, possibly by attenuating lysosomal degradation of GRN
  • ADAM15 participates likely in fertilization through a physical interaction with GRN
  • RETN and GRN represent novel and putative regulators of the fat-brain axis by their ability to cross the blood-brain barrier (BBB) under physiological and pathophysiological condition
  • role of GRN in PSAP lysosomal trafficking, suggesting that impaired lysosomal trafficking of PSAP is an underlying disease mechanism for NCL and FTLD due to GRN mutations
  • GRN and PSAP facilitate each other lysosomal trafficking and interaction between GRN and PSAP is mediated by granulins and the linker region between saposin B and C
  • cell & other
    REGULATION
    Other SORT1 regulates the levels of brain progranulin (PGRN)
    ASSOCIATED DISORDERS
    corresponding disease(s) FTDU17 , CLN11
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in corticoadrenal carcinoma (malignant progression)
    constitutional somatic mutation      
    mutations creating null alleles cause tau-negative frontotemporal dementia
    tumoral     --over  
    in uterine leiomyosarcoma
    constitutional   deletion    
    sufficient to cause neurodegeneration
    constitutional   deletion    
    deleted with RUNDC3A in frontotemporal dementia
    constitutional       loss of function
    leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury
    tumoral     --over  
    in hepatocellular carcinoma but not in the adjacent non-tumor
    constitutional     --low  
    in 65 p100 of children with autism
    constitutional     --over  
    increased GRN in the skin of amyotrophic lateral sclerosis, related to the disease process and metabolic alteration of GRN may take place in the skin of patients with ALS
    constitutional     --over  
    in Alzheimer disease brains, whereas TMEM106B mRNA levels were decreased
    constitutional     --low gain of function
    both PSAP reduction and overexpression lead to significantly elevated extracellular GRN levels
    Susceptibility
  • to Alzheimer disease and Parkinson disease
  • to frontotemporal lobar degeneration (FTLD)
  • Variant & Polymorphism other
  • mutation frequency of GRN mutation was 6.6p100 in FTLD
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    obesity  
    may be a promising therapeutic target for obesity
    osteoarticular  
    potential target for developing and optimizing the therapeutic application in cartilage repair and arthritic disorders
    cancerdigestiveliver
    potential therapeutic target for HCC
    neurologyneurodegenerative 
    therapeutic target for neurodegenerative diseases including motor neuron disease
    immunologyautoimmunearticular
    promising therapeutic target for rheumatoid arthritis
    ANIMAL & CELL MODELS