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This gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of this gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008]
SHH (Sonic Hedgehog Signaling Molecule) is a Protein Coding gene. Diseases associated with SHH include Solitary Median Maxillary Central Incisor and Holoprosencephaly 3. Among its related pathways are Development_Hedgehog and PTH signaling pathways in bone and cartilage development and Signaling by GPCR. Gene Ontology (GO) annotations related to this gene include calcium ion binding. An important paralog of this gene is IHH.
The Hedgehog (Hh) signaling pathway is crucial in the development of all animals. In the embryo, it regulates morphogenesis of a variety of tissues and organs; in the adult, it controls stem cell proliferation. There are three known human Hh proteins: Shh, Dhh and Ihh.
GeneHancer (GH) Identifier | GH Type | GH Score |
GH Sources | Gene Association Score | Total Score | TSS distance (kb) | Number of Genes Away | Size (kb) | Transcription Factor Binding Sites |
Gene Targets |
---|---|---|---|---|---|---|---|---|---|---|
GH07J155806 | Promoter/Enhancer | 1.7 | EPDnew Ensembl ENCODE dbSUPER | 600.7 | +3.9 | 3900 | 3.3 | HNRNPL GATAD2A ATF7 REST TFE3 KDM1A ZIC2 RBFOX2 RXRB SP1 | SHH lnc-CNPY1-12 RBM33 | |
GH07J155813 | Promoter/Enhancer | 1.3 | EPDnew Ensembl dbSUPER | 600.7 | +0.2 | 162 | 0.6 | PRDM10 PRDM1 POLR2A EZH2 GTF2F1 ZNF341 ATF7 RAD21 ZBTB10 ZBTB26 | SHH lnc-CNPY1-12 RBM33 | |
GH07J155811 | Enhancer | 0.5 | ENCODE | 600.7 | +1.4 | 1381 | 0.2 | EZH2 ZNF341 CEBPB ATF4 GLIS1 ZNF398 KLF1 HLF | SHH lnc-CNPY1-12 RBM33 | |
GH07J155814 | Enhancer | 0.5 | ENCODE | 600.7 | +0.7 | 741 | 0.2 | EZH2 ZBTB26 ZFHX2 KLF17 GLIS1 KLF1 | SHH lnc-CNPY1-12 RBM33 | |
GH07J155203 | Promoter/Enhancer | 1.6 | Ensembl ENCODE dbSUPER | 5.9 | +605.6 | 605605 | 5.8 | RNF2 ARHGAP35 SP1 CREB1 HNRNPL ATF7 PRDM10 ZNF629 LEF1 IKZF1 | PAXIP1-AS2 PAXIP1 RBM33 PAXIP1-DT ENSG00000273183 ENSG00000228521 INSIG1 SHH ENSG00000287865 lnc-PAXIP1-23 |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0005113 | patched binding | IEA,IDA | 8906787 |
GO:0005509 | calcium ion binding | IBA,IDA | 19561609 |
GO:0005515 | protein binding | IPI | 19561609 |
GO:0005539 | glycosaminoglycan binding | IEA | -- |
GO:0008233 | peptidase activity | IEA | -- |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0005576 | extracellular region | TAS | -- |
GO:0005615 | extracellular space | IEA,ISS | -- |
GO:0005788 | endoplasmic reticulum lumen | TAS | -- |
GO:0005829 | cytosol | TAS | -- |
GO:0005886 | plasma membrane | TAS | -- |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | Regulation of activated PAK-2p34 by proteasome mediated degradation | ||
2 | Signaling by Hedgehog | ||
3 | HIV Life Cycle |
.45
|
|
4 | Signaling events mediated by the Hedgehog family | ||
5 | Signaling by GPCR |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000122 | negative regulation of transcription by RNA polymerase II | IEA,ISS | -- |
GO:0001525 | angiogenesis | IEA | -- |
GO:0001569 | branching involved in blood vessel morphogenesis | IEA,ISS | -- |
GO:0001570 | vasculogenesis | IEA,ISS | -- |
GO:0001656 | metanephros development | IEA,ISS | -- |
Name | Status | Disease Links | Group | Role | Mechanism of Action | Clinical Trials |
---|---|---|---|---|---|---|
Cisplatin | Approved | Pharma | Inhibits DNA synthesis,chemotherapy drug, Potent pro-apoptotic anticancer agent; activates caspase-3, Platinum | 3412 | ||
Cyclophosphamide | Approved, Investigational | Pharma | Nitrogen mustard alkylating agent and prodrug. | 3670 | ||
Epinephrine | Approved, Vet_approved | Pharma | 1364 | |||
Gemcitabine | Approved | Pharma | Ribonucleotide reductase and DNA synthesis inhibitor, Nucleoside Analogs | 2451 | ||
leucovorin | Approved | Pharma | 3692,1548 |
Compound | Action | Cas Number |
---|---|---|
20(S)-Hydroxycholesterol | Allosteric activator of Hedgehog (Hh) signaling; induces Smo accumulation | 516-72-3 |
Cyclopamine | Inhibitor of Hedgehog (Hh) signaling | 4449-51-8 |
Jervine | Inhibitor of Hedgehog (Hh) signaling; binds directly to Smo | 469-59-0 |
SANT-1 | Inhibitor of hedgehog (Hh) signaling; antagonizes smoothened activity | 304909-07-7 |
SANT-2 | Inhibitor of Hedgehog (Hh) signaling; antagonizes smoothened activity | 329196-48-7 |
Compound | Action | Cas Number |
---|---|---|
20(S)-Hydroxycholesterol | 516-72-3 | |
AY 9944 dihydrochloride | Hedgehog Inhibitor | 366-93-8 |
Ciliobrevin A | Hh pathway antagonist | 302803-72-1 |
Cyclopamine | Hedgehog (Hh) signaling Inhibitor | 4449-51-8 |
GANT61 | GLI antagonist | 500579-04-4 |
GDC-0449 (Vismodegib) | Hedgehog antagonist,potent and selective | 879085-55-9 |
HPI 1 | Hh signaling inhibitor | 599150-20-6 |
Jervine | Hedgehog signaling Inhibitor | 469-59-0 |
JK 184 | Hh signaling inhibitor | 315703-52-7 |
LY2940680 | Hedgehog/SMO antagonist,inhibits Hh signaling | 1258861-20-9 |
PF-5274857 | Smo antagonist,potent and selective | 1373615-35-0 |
Purmorphamine | Hedgehog agonist | 483367-10-8 |
SAG | Hh and Smo agonist | 912545-86-9 |
SANT-1 | Shh inhibitor,potent and cell-permeable | 304909-07-7 |
SANT-2 | 329196-48-7 | |
U 18666A | inhibitor of cholesterol transport and synthesis | 3039-71-2 |
This gene was present in the common ancestor of animals.
Organism | Taxonomy | Gene | Similarity | Type | Details |
---|---|---|---|---|---|
Chimpanzee (Pan troglodytes) |
Mammalia | SHH 30 |
|
||
-- 31 |
|
ManyToMany | |||
Dog (Canis familiaris) |
Mammalia | SHH 30 31 |
|
OneToOne | |
Mouse (Mus musculus) |
Mammalia | Shh 30 17 31 |
|
OneToOne | |
Rat (Rattus norvegicus) |
Mammalia | Shh 30 |
|
||
Oppossum (Monodelphis domestica) |
Mammalia | SHH 31 |
|
OneToOne | |
Cow (Bos Taurus) |
Mammalia | SHH 30 31 |
|
OneToOne | |
Platypus (Ornithorhynchus anatinus) |
Mammalia | -- 31 |
|
ManyToMany | |
Chicken (Gallus gallus) |
Aves | SHH 30 31 |
|
OneToOne | |
Lizard (Anolis carolinensis) |
Reptilia | SHH 31 |
|
OneToOne | |
Tropical Clawed Frog (Silurana tropicalis) |
Amphibia | shh 30 |
|
||
African clawed frog (Xenopus laevis) |
Amphibia | LOC398047 30 |
|
||
Zebrafish (Danio rerio) |
Actinopterygii | shha 31 |
|
OneToMany | |
shhb 30 31 |
|
OneToMany | |||
shh 30 |
|
||||
African malaria mosquito (Anopheles gambiae) |
Insecta | AgaP_AGAP001412 30 |
|
||
Fruit Fly (Drosophila melanogaster) |
Insecta | hh 30 31 32 |
|
OneToMany | |
Sea Squirt (Ciona savignyi) |
Ascidiacea | -- 31 |
|
ManyToMany | |
-- 31 |
|
ManyToMany |
SNP ID | Clinical significance and condition | Chr 07 pos | Variation | AA Info | Type |
---|---|---|---|---|---|
646865 | Pathogenic: Holoprosencephaly 3 | 155,806,434(-) | C/CGTAGT | FRAMESHIFT_VARIANT,NON_CODING_TRANSCRIPT_VARIANT | |
651974 | Likely Pathogenic: Holoprosencephaly 3 | 155,811,821(-) | A/G | SPLICE_DONOR_VARIANT | |
666320 | Likely Pathogenic: Microphthalmia, isolated, with coloboma 5 | 155,803,187(-) | C/A | NONSENSE,INTRON_VARIANT | |
667597 | Benign: not provided | 155,805,972(-) | T/C | INTRON_VARIANT | |
669009 | Benign/Likely Benign: not provided | 156,791,369(-) | G/C | INTRON_VARIANT |
Variant ID | Type | Subtype | PubMed ID |
---|---|---|---|
esv2663062 | CNV | deletion | 23128226 |
nsv1075489 | CNV | deletion | 25765185 |
nsv509227 | CNV | insertion | 20534489 |
nsv951662 | CNV | deletion | 24416366 |
Disorder | Aliases | PubMed IDs |
---|---|---|
solitary median maxillary central incisor |
|
|
holoprosencephaly 3 |
|
|
microphthalmia, isolated, with coloboma 5 |
|
|
autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome |
|
|
schizencephaly |
|
|