Human Gene GLI3 (ENST00000395925.8) from GENCODE V43
  Description: Homo sapiens GLI family zinc finger 3 (GLI3), mRNA. (from RefSeq NM_000168)
RefSeq Summary (NM_000168): This gene encodes a protein which belongs to the C2H2-type zinc finger proteins subclass of the Gli family. They are characterized as DNA-binding transcription factors and are mediators of Sonic hedgehog (Shh) signaling. The protein encoded by this gene localizes in the cytoplasm and activates patched Drosophila homolog (PTCH) gene expression. It is also thought to play a role during embryogenesis. Mutations in this gene have been associated with several diseases, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B. [provided by RefSeq, Jul 2008]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments.
Gencode Transcript: ENST00000395925.8
Gencode Gene: ENSG00000106571.15
Transcript (Including UTRs)
   Position: hg38 chr7:41,960,949-42,237,209 Size: 276,261 Total Exon Count: 15 Strand: -
Coding Region
   Position: hg38 chr7:41,964,330-42,223,253 Size: 258,924 Coding Exon Count: 14 

Page IndexSequence and LinksUniProtKB CommentsPrimersMalaCardsCTD
RNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther SpeciesGO Annotations
mRNA DescriptionsPathwaysOther NamesGeneReviewsMethods
Data last updated at UCSC: 2023-02-17 13:02:02

-  Sequence and Links to Tools and Databases
Genomic Sequence (chr7:41,960,949-42,237,209)mRNA (may differ from genome)Protein (1580 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
AlphaFoldBioGPSCGAPEnsemblEntrez GeneExonPrimer

-  Comments and Description Text from UniProtKB
DESCRIPTION: RecName: Full=Transcriptional activator GLI3; AltName: Full=GLI3 form of 190 kDa; Short=GLI3-190; AltName: Full=GLI3 full length protein; Short=GLI3FL; Contains: RecName: Full=Transcriptional repressor GLI3R; AltName: Full=GLI3 C-terminally truncated form; AltName: Full=GLI3 form of 83 kDa; Short=GLI3-83;
FUNCTION: Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.
SUBUNIT: The full-length GLI3 form (GLI3FL) interacts with SUFU and this interaction regulates the formation of either repressor or activator forms of GLI3. Its association with SUFU is regulated by Hh signaling and dissociation of the SUFU-GLI3 interaction requires the presence of the ciliary motor KIF3A (By similarity). Interacts with KIF7. The activator form of GLI3 (GLI3A) but not the repressor form (GLI3R) can interact with TRPS1. The phosphorylated form interacts with BTRC. Interacts with ZIC1. Interacts with ZIC3 (via C2H2-type domains 3, 4 and 5); the interaction enhances its transcriptional activity.
INTERACTION: P46684:Zic1 (xeno); NbExp=2; IntAct=EBI-308055, EBI-308006; Q62520:Zic2 (xeno); NbExp=2; IntAct=EBI-308055, EBI-308076;
SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cell projection, cilium. Note=GLI3FL is localized predominantly in the cytoplasm while GLI3R resides mainly in the nucleus. Ciliary accumulation requires the presence of KIF7 and SMO. Translocation to the nucleus is promoted by interaction with ZIC1.
TISSUE SPECIFICITY: Is expressed in a wide variety of normal adult tissues, including lung, colon, spleen, placenta, testis, and myometrium.
PTM: Phosphorylated on multiple sites by protein kinase A (PKA) and phosphorylation by PKA primes further phosphorylation by CK1 and GSK3. Phosphorylation is essential for its proteolytic processing.
PTM: Transcriptional repressor GLI3R, a C-terminally truncated form, is generated from the full-length GLI3 protein (GLI3FL/GLI3- 190) through proteolytic processing. This process requires PKA- primed phosphorylation of GLI3, ubiquitination of GLI3 and the presence of BTRC. GLI3FL is complexed with SUFU in the cytoplasm and is maintained in a neutral state. Without the Hh signal, the SUFU-GLI3 complex is recruited to cilia, leading to the efficient processing of GLI3FL into GLI3R. GLI3R formation leads to its dissociation from SUFU, allowing it to translocate into the nucleus, and repress Hh target genes. When Hh signaling is initiated, SUFU dissociates from GLI3FL and this has two consequences. First, GLI3R production is halted. Second, free GLI3FL translocates to the nucleus, where it is phosphorylated, destabilized, and converted to a transcriptional activator (GLI3A). Phosphorylated in vitro by ULK3.
DISEASE: Defects in GLI3 are the cause of Greig cephalo-poly- syndactyly syndrome (GCPS) [MIM:175700]. GCPS is an autosomal dominant disorder affecting limb and craniofacial development. It is characterized by pre- and postaxial polydactyly, syndactyly of fingers and toes, macrocephaly and hypertelorism.
DISEASE: Defects in GLI3 are a cause of Pallister-Hall syndrome (PHS) [MIM:146510]. PHS is characterized by a wide range of clinical manifestations. It mainly associates central or postaxial polydactyly, syndactyly, and hypothalamic hamartoma. Malformations are frequent in the viscera, e.g. anal atresia, bifid uvula, congenital heart malformations, pulmonary or renal dysplasia. It is an autosomal dominant disorder.
DISEASE: Defects in GLI3 are a cause of polydactyly postaxial type A1 (PAPA1) [MIM:174200]. A trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is well formed and articulates with the fifth, or extra, metacarpal/metatarsal, and thus it is usually functional.
DISEASE: Defects in GLI3 are a cause of polydactyly postaxial type B polydactyly (PAPB) [MIM:174200]. A trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is not well formed and is frequently in the form of a skin.
DISEASE: Defects in GLI3 are a cause of polydactyly preaxial type 4 (POP4) [MIM:174700]. Polydactyly preaxial type 4 (i.e. polydactyly on the radial/tibial side of the hand/foot) covers a heterogeneous group of entities. In preaxial polydactyly type IV, the thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4.
SIMILARITY: Belongs to the GLI C2H2-type zinc-finger protein family.
SIMILARITY: Contains 5 C2H2-type zinc fingers.
SEQUENCE CAUTION: Sequence=AAA52564.1; Type=Frameshift; Positions=1549;
WEB RESOURCE: Name=GeneReviews; URL="";

-  Primer design for this transcript

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-  MalaCards Disease Associations
  MalaCards Gene Search: GLI3
Diseases sorted by gene-association score: greig cephalopolysyndactyly syndrome* (1712), polydactyly, postaxial, types a1 and b* (1332), pallister-hall syndrome* (1062), polydactyly, preaxial, type iv* (1000), hypothalamic hamartomas, somatic* (550), tibial hemimelia, bilateral* (350), postaxial polydactyly type a, unilateral* (350), polysyndactyly, bilateral* (350), polysyndactyly, unilateral* (350), postaxial polydactyly type b, bilateral* (350), postaxial polydactyly type b, unilateral* (350), acrocallosal syndrome* (272), postaxial polydactyly type a, bilateral* (247), gli3-related disorders* (100), polydactyly (40), chromosome 2q35 duplication syndrome (15), holoprosencephaly 4 (11), tibial hemimelia (10), synovial chondromatosis (10), esophageal atresia (9), basal cell carcinoma (9), bifid uvula (8), talipes equinovarus (8), synostosis (8), omphalocele (7), mckusick-kaufman syndrome (7), tracheoesophageal fistula (7), apert syndrome (6), congenital heart defects, hamartomas of tongue, and polysyndactyly (6), xeroderma pigmentosum group e (6), ohdo syndrome (5), infratentorial cancer (4), basal cell nevus syndrome (4), nominal aphasia (4), hajdu-cheney syndrome (4), brain cancer (2), tooth agenesis (2), physical disorder (2), bone development disease (2), dementia, frontotemporal (1), amyotrophic lateral sclerosis 1 (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 9.27 RPKM in Uterus
Total median expression: 145.57 RPKM

View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -128.10281-0.456 Picture PostScript Text
3' UTR -883.743381-0.261 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR007087 - Znf_C2H2
IPR015880 - Znf_C2H2-like
IPR013087 - Znf_C2H2/integrase_DNA-bd

Pfam Domains:
PF00096 - Zinc finger, C2H2 type

ModBase Predicted Comparative 3D Structure on P10071
The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
Protein SequenceProtein Sequence    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000977 RNA polymerase II regulatory region sequence-specific DNA binding
GO:0000978 RNA polymerase II core promoter proximal region sequence-specific DNA binding
GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding
GO:0001077 transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
GO:0003676 nucleic acid binding
GO:0003677 DNA binding
GO:0003682 chromatin binding
GO:0003700 transcription factor activity, sequence-specific DNA binding
GO:0005515 protein binding
GO:0008013 beta-catenin binding
GO:0035035 histone acetyltransferase binding
GO:0042826 histone deacetylase binding
GO:0043565 sequence-specific DNA binding
GO:0046872 metal ion binding

Biological Process:
GO:0000122 negative regulation of transcription from RNA polymerase II promoter
GO:0001656 metanephros development
GO:0001658 branching involved in ureteric bud morphogenesis
GO:0001701 in utero embryonic development
GO:0001822 kidney development
GO:0002052 positive regulation of neuroblast proliferation
GO:0006351 transcription, DNA-templated
GO:0006355 regulation of transcription, DNA-templated
GO:0006366 transcription from RNA polymerase II promoter
GO:0007224 smoothened signaling pathway
GO:0007389 pattern specification process
GO:0007411 axon guidance
GO:0007417 central nervous system development
GO:0007420 brain development
GO:0007442 hindgut morphogenesis
GO:0007507 heart development
GO:0008285 negative regulation of cell proliferation
GO:0009952 anterior/posterior pattern specification
GO:0009953 dorsal/ventral pattern formation
GO:0009954 proximal/distal pattern formation
GO:0010468 regulation of gene expression
GO:0016485 protein processing
GO:0021513 spinal cord dorsal/ventral patterning
GO:0021522 spinal cord motor neuron differentiation
GO:0021537 telencephalon development
GO:0021543 pallium development
GO:0021544 subpallium development
GO:0021631 optic nerve morphogenesis
GO:0021766 hippocampus development
GO:0021775 smoothened signaling pathway involved in ventral spinal cord interneuron specification
GO:0021776 smoothened signaling pathway involved in spinal cord motor neuron cell fate specification
GO:0021798 forebrain dorsal/ventral pattern formation
GO:0021801 cerebral cortex radial glia guided migration
GO:0021819 layer formation in cerebral cortex
GO:0021861 forebrain radial glial cell differentiation
GO:0021915 neural tube development
GO:0022018 lateral ganglionic eminence cell proliferation
GO:0030318 melanocyte differentiation
GO:0030324 lung development
GO:0030326 embryonic limb morphogenesis
GO:0030850 prostate gland development
GO:0030879 mammary gland development
GO:0030900 forebrain development
GO:0032332 positive regulation of chondrocyte differentiation
GO:0033077 T cell differentiation in thymus
GO:0035108 limb morphogenesis
GO:0035295 tube development
GO:0042060 wound healing
GO:0042127 regulation of cell proliferation
GO:0042307 positive regulation of protein import into nucleus
GO:0042475 odontogenesis of dentin-containing tooth
GO:0042733 embryonic digit morphogenesis
GO:0042981 regulation of apoptotic process
GO:0043010 camera-type eye development
GO:0043066 negative regulation of apoptotic process
GO:0043585 nose morphogenesis
GO:0043586 tongue development
GO:0043627 response to estrogen
GO:0045060 negative thymic T cell selection
GO:0045595 regulation of cell differentiation
GO:0045596 negative regulation of cell differentiation
GO:0045665 negative regulation of neuron differentiation
GO:0045669 positive regulation of osteoblast differentiation
GO:0045879 negative regulation of smoothened signaling pathway
GO:0045892 negative regulation of transcription, DNA-templated
GO:0045893 positive regulation of transcription, DNA-templated
GO:0045944 positive regulation of transcription from RNA polymerase II promoter
GO:0046638 positive regulation of alpha-beta T cell differentiation
GO:0046639 negative regulation of alpha-beta T cell differentiation
GO:0048557 embryonic digestive tract morphogenesis
GO:0048566 embryonic digestive tract development
GO:0048568 embryonic organ development
GO:0048589 developmental growth
GO:0048593 camera-type eye morphogenesis
GO:0048598 embryonic morphogenesis
GO:0048646 anatomical structure formation involved in morphogenesis
GO:0048663 neuron fate commitment
GO:0048704 embryonic skeletal system morphogenesis
GO:0048709 oligodendrocyte differentiation
GO:0048754 branching morphogenesis of an epithelial tube
GO:0048839 inner ear development
GO:0048856 anatomical structure development
GO:0060021 palate development
GO:0060173 limb development
GO:0060364 frontal suture morphogenesis
GO:0060366 lambdoid suture morphogenesis
GO:0060367 sagittal suture morphogenesis
GO:0060594 mammary gland specification
GO:0060831 smoothened signaling pathway involved in dorsal/ventral neural tube patterning
GO:0060840 artery development
GO:0060873 anterior semicircular canal development
GO:0060875 lateral semicircular canal development
GO:0061005 cell differentiation involved in kidney development
GO:0070242 thymocyte apoptotic process
GO:0090090 negative regulation of canonical Wnt signaling pathway
GO:0097421 liver regeneration
GO:1903010 regulation of bone development

Cellular Component:
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005737 cytoplasm
GO:0005829 cytosol
GO:0005929 cilium
GO:0005930 axoneme
GO:0016607 nuclear speck
GO:0017053 transcriptional repressor complex
GO:0042995 cell projection
GO:0097542 ciliary tip
GO:0097546 ciliary base
GO:0016592 mediator complex

-  Descriptions from all associated GenBank mRNAs
  M57609 - Human DNA-binding protein (GLI3) mRNA, complete cds.
AK299299 - Homo sapiens cDNA FLJ50841 complete cds, highly similar to Zinc finger protein GLI3.
BC117168 - Homo sapiens GLI family zinc finger 3, mRNA (cDNA clone MGC:150777 IMAGE:40125719), complete cds.
BC113616 - Homo sapiens GLI family zinc finger 3, mRNA (cDNA clone MGC:142176 IMAGE:8322668), complete cds.
AB489183 - Synthetic construct DNA, clone: pF1KE1055, Homo sapiens GLI3 gene for GLI-Kruppel family member GLI3, without stop codon, in Flexi system.
AK308429 - Homo sapiens cDNA, FLJ98377.
BC032660 - Homo sapiens cDNA clone IMAGE:5532335, partial cds.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04340 - Hedgehog signaling pathway
hsa05200 - Pathways in cancer
hsa05217 - Basal cell carcinoma

BioCarta from NCI Cancer Genome Anatomy Project
h_shhPathway - Sonic Hedgehog (Shh) Pathway

Reactome (by CSHL, EBI, and GO)

Protein P10071 (Reactome details) participates in the following event(s):

R-HSA-5612508 GLI3R binds the PTCH1 promoter
R-HSA-5617408 GLI3R binds the GLI1 promoter
R-HSA-5617410 GLI3R binds the GLI2 promoter
R-HSA-9008215 RUNX2 binds GLI3R
R-HSA-5610723 GLI proteins bind SUFU
R-HSA-5610720 PKA phosphorylates GLI3
R-HSA-5635842 ULK3 phosphorylates GLI
R-HSA-5635859 GLI:SUFU dissociates
R-HSA-5610732 GSK3 phosphorylates p-GLI3
R-HSA-5610722 CK1 phosphorylates p-GLI3
R-HSA-5610746 SCF(beta-TrCP) ubiquitinates p-GLI3
R-HSA-5635845 GLI proteins bind CDC73
R-HSA-5635846 GLI proteins bind GLI1 gene
R-HSA-5635848 GLI proteins bind PTCH1 gene
R-HSA-5635855 phosphorylated GLI proteins bind SPOP:CUL3:RBX1
R-HSA-5635856 SPOP:CUL3:RBX1 ubiquitinates GLI2,3
R-HSA-5610787 Hedgehog 'off' state
R-HSA-5610785 GLI3 is processed to GLI3R by the proteasome
R-HSA-8940973 RUNX2 regulates osteoblast differentiation
R-HSA-5632684 Hedgehog 'on' state
R-HSA-5358351 Signaling by Hedgehog
R-HSA-8941326 RUNX2 regulates bone development
R-HSA-5635851 GLI proteins bind promoters of Hh responsive genes to promote transcription
R-HSA-162582 Signal Transduction
R-HSA-8878166 Transcriptional regulation by RUNX2
R-HSA-212436 Generic Transcription Pathway
R-HSA-73857 RNA Polymerase II Transcription
R-HSA-74160 Gene expression (Transcription)

-  Other Names for This Gene
  Alternate Gene Symbols: A4D1W1, ENST00000395925.1, ENST00000395925.2, ENST00000395925.3, ENST00000395925.4, ENST00000395925.5, ENST00000395925.6, ENST00000395925.7, GLI3_HUMAN, NM_000168, O75219, P10071, Q17RW4, Q75MT0, Q75MU9, Q9UDT5, Q9UJ39, uc011kbh.1, uc011kbh.2, uc011kbh.3, uc011kbh.4
UCSC ID: ENST00000395925.8
RefSeq Accession: NM_000168
Protein: P10071 (aka GLI3_HUMAN)
CCDS: CCDS5465.1

-  GeneReviews for This Gene
  GeneReviews article(s) related to gene GLI3:
gcps (Greig Cephalopolysyndactyly Syndrome)
phs (GLI3-Related Pallister-Hall Syndrome)
tef-ov (Esophageal Atresia/Tracheoesophageal Fistula Overview)

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.