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SHH (Sonic hedgehog)

Written2002-02Thierry Magnaldo
CNRS, UPR 2169, Instabilit@eacute; Génétique et Cancer, Institut André LWOFF, 7, rue Guy Moquet, 94801 Villejuif, France

(Note : for Links provided by Atlas : click)

Identity

Alias_namesHPE3
HLP3
sonic hedgehog (Drosophila) homolog
Alias_symbol (synonym)HHG1
SMMCI
TPT
TPTPS
MCOPCB5
Other alias
HGNC (Hugo) SHH
LocusID (NCBI) 6469
Atlas_Id 378
Location 7q36.3  [Link to chromosome band 7q36]
Location_base_pair Starts at 155799984 and ends at 155809072 bp from pter ( according to hg19-Feb_2009)  [Mapping SHH.png]
Local_order Markers: RH69762, StSG39143
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
DNAJB6 (7q36.3) / SHH (7q36.3)SHH (7q36.3) / TSPAN14 (10q23.1)
Note Sonic hedgehog (SHH) is the vertebrate orthologue of Hedeghog (Hh) a morphogen signalling molecule discovered in a mutant drosophila (fruit fly). In addition to SHH, two other distinct Hh homologues have been cloned in vertebrates, Indian Hedgehog (Ihh) and (Dhh).

DNA/RNA

Description 3 exons, all 3 coding, cDNA to mRNA is 1576 bp
Transcription coding sequence : nucleotides 152 to 1540. Two transcription start sites have been described.

Protein

Description SHH is a secreted protein synthesised as a precursor molecule of 462 amino acids (45kDa); it harbors a signal sequence of 23 amino acids. Following removal of the signal sequence, a cholestreol-mediated autocatalystic cleavage results in a NH2 and a COOH subportions (N-SHH and C-SHH, respectively 19kDa and 25 kDa). N-SHH emcompasses amino acids 24-196. C-SHH encompasses amino acids 197-463. The C-SHH moeity bears the cholesterol transferase activity. Upon processing, the cholestreol molecule is covalently transfered to the C terminus of N-SHH through a nucleophilic substitution. Post-translational processing of N-SHH is thought to be necessary to its correct spatial distribution and effects during embryonic patterning. Except its role in the autocatalytic cleavage of precursor SHH, no biological activity of C-SHH has been evidenced.
Expression SHH is the most broadly expressed member the hedgehog family. It is involved in the development of axial skeleton, notochord, spinal cord, floor plate, gut endoderm, and posterior limb (see also: Skeletal development in human: a model for the study of developmental genes .Ihh and Dhh play distinctive roles in the development of cartilage, and male germ cells respectively. In the adult, SHH plays roles in the hair follicle growth and cycle.
Localisation SHH is secreted from producing cells to reach the surface of target cells were it interacts with its receptor, the multipass transmembrane protein PATCHED.
Function SHH is implicated in segment polarisation. SHH biochemical function is the binding of PATCHED. This interaction modulates the activity of a third transmembrane protein called Smothened (SMO) apparented with G proteins-coupled receptors. SHH binding results in activation of the SHH/PATCHED pathway which eventually results in the modulation of the balance between cell proliferation and differentiation. In the absence of SHH, PATCHED acts as a constitutive repressor of the activity of SMO by posttranscriptionnal modifications. In contrast, the presence of SHH releaves PATCHED-mediated SMO inhibition and results in cell proliferation and transriptional activation of SHH target genes (PATCHED, Wingless, DPP, in Drosophila ; PATCHED, Wnt, BMPs, in vertebrates) involving Ci (Drosophila) or Gli (Gli-1, 2, 3, vertebrates) transcriptional factors. Most notably, SHH-induced SMO activation proceeds with transcription of PATCHED itself, suggesting a retroregulation loop, and hence a narrow maintenance of both free SHH and PATCHED/SMO complex concentration at the cell surface.
The important role of the SHH/PATCHED pathway in development and tissue homeostasis is attested by genetic disorders linked to specific dysregulation of this pathway. Familial mutations of PATCHED are linked to the Gorlin's or Nevoid Basal cell carcinoma syndrome. SHH mutations may result in sporadic or familial Holoproencepaly HPE (see below).
Homology Alignement of full length human SHH and human IHH cDNAs reveals 71.608 % identities (GCG, Bestfit).

Mutations

Germinal To the contrary of PATCHED, which mutation may result in familial predisposition to basal cell carcinoma and meduloblastoma, SHH mutations only result in developmental abnormalities. To date, there is actually no clear evidence that SHH mutation may be " naturally " associated with cancer. However, transgenic mice overexpressing SHH in the epidermal layer of skin develop basal cell carcinoma-like tumors.
Most SHH mutations that have been identified are associated with sporadic or familial cases of holoproencephaly (HPE, 1/133000 to 1/16000 viable birth) and Solitary Median Maxillary Central Incisor (SMMCI). Mutations are sparse over the SHH coding region. All types of mutation have been described. No evident correlation between mutation types and location, and patient phenotypes can be drawn

Bibliography

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PMID 10525354
 

Citation

This paper should be referenced as such :
Magnaldo, T
SHH (Sonic hedgehog)
Atlas Genet Cytogenet Oncol Haematol. 2002;6(2):117-121.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SHHID378.html

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  DNAJB6/SHH (7q36)

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Holoprosencephaly-diencephalic hamartoblastoma (HDH).

External links

Nomenclature
HGNC (Hugo)SHH   10848
Cards
AtlasSHHID378
Entrez_Gene (NCBI)SHH  6469  sonic hedgehog signaling molecule
AliasesHHG1; HLP3; HPE3; MCOPCB5; 
SMMCI; ShhNC; TPT; TPTPS
GeneCards (Weizmann)SHH
Ensembl hg19 (Hinxton)ENSG00000164690 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000164690 [Gene_View]  ENSG00000164690 [Sequence]  chr7:155799984-155809072 [Contig_View]  SHH [Vega]
ICGC DataPortalENSG00000164690
TCGA cBioPortalSHH
AceView (NCBI)SHH
Genatlas (Paris)SHH
WikiGenes6469
SOURCE (Princeton)SHH
Genetics Home Reference (NIH)SHH
Genomic and cartography
GoldenPath hg38 (UCSC)SHH  -     chr7:155799984-155809072 -  7q36.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SHH  -     7q36.3   [Description]    (hg19-Feb_2009)
GoldenPathSHH - 7q36.3 [CytoView hg19]  SHH - 7q36.3 [CytoView hg38]
ImmunoBaseENSG00000164690
Mapping of homologs : NCBISHH [Mapview hg19]  SHH [Mapview hg38]
OMIM142945   147250   269160   600725   611638   
Gene and transcription
Genbank (Entrez)AI192528 AY927450 AY927451 AY927452 AY927453
RefSeq transcript (Entrez)NM_000193 NM_001310462
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SHH
Cluster EST : UnigeneHs.738995 [ NCBI ]
CGAP (NCI)Hs.738995
Alternative Splicing GalleryENSG00000164690
Gene ExpressionSHH [ NCBI-GEO ]   SHH [ EBI - ARRAY_EXPRESS ]   SHH [ SEEK ]   SHH [ MEM ]
Gene Expression Viewer (FireBrowse)SHH [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6469
GTEX Portal (Tissue expression)SHH
Human Protein AtlasENSG00000164690-SHH [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15465   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ15465  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ15465
Splice isoforms : SwissVarQ15465
PhosPhoSitePlusQ15465
Domaine pattern : Prosite (Expaxy)INTEIN_N_TER (PS50817)   
Domains : Interpro (EBI)Hedgehog    Hedgehog_sig/DD-Pept_Zn-bd_sf    Hedgehog_signalling_dom    Hint_dom    Hint_dom_C    Hint_dom_N    Hint_dom_sf    Intein_N   
Domain families : Pfam (Sanger)HH_signal (PF01085)    Hint (PF01079)   
Domain families : Pfam (NCBI)pfam01085    pfam01079   
Domain families : Smart (EMBL)HintC (SM00305)  HintN (SM00306)  
Conserved Domain (NCBI)SHH
DMDM Disease mutations6469
Blocks (Seattle)SHH
PDB (RSDB)3HO5    3M1N    3MXW   
PDB Europe3HO5    3M1N    3MXW   
PDB (PDBSum)3HO5    3M1N    3MXW   
PDB (IMB)3HO5    3M1N    3MXW   
Structural Biology KnowledgeBase3HO5    3M1N    3MXW   
SCOP (Structural Classification of Proteins)3HO5    3M1N    3MXW   
CATH (Classification of proteins structures)3HO5    3M1N    3MXW   
SuperfamilyQ15465
Human Protein Atlas [tissue]ENSG00000164690-SHH [tissue]
Peptide AtlasQ15465
HPRD02838
IPIIPI00017480   IPI00893003   IPI00892712   IPI00894434   
Protein Interaction databases
DIP (DOE-UCLA)Q15465
IntAct (EBI)Q15465
FunCoupENSG00000164690
BioGRIDSHH
STRING (EMBL)SHH
ZODIACSHH
Ontologies - Pathways
QuickGOQ15465
Ontology : AmiGOnegative regulation of transcription by RNA polymerase II  branching involved in blood vessel morphogenesis  vasculogenesis  metanephros development  branching involved in ureteric bud morphogenesis  cell fate specification  cell fate specification  neural crest cell migration  heart looping  positive regulation of neuroblast proliferation  osteoblast development  lymphoid progenitor cell differentiation  determination of left/right asymmetry in lateral mesoderm  patched binding  patched binding  calcium ion binding  calcium ion binding  protein binding  glycosaminoglycan binding  extracellular region  extracellular space  extracellular space  extracellular space  endoplasmic reticulum lumen  cytosol  plasma membrane  endocytosis  smoothened signaling pathway  smoothened signaling pathway  smoothened signaling pathway  positive regulation of hh target transcription factor activity  cell-cell signaling  pattern specification process  ectoderm development  neuroblast proliferation  axon guidance  central nervous system development  ventral midline development  hindgut morphogenesis  heart development  blood coagulation  androgen metabolic process  peptidase activity  zinc ion binding  positive regulation of cell proliferation  positive regulation of cell proliferation  embryonic pattern specification  polarity specification of anterior/posterior axis  dorsal/ventral pattern formation  cell surface  regulation of gene expression  oligodendrocyte development  striated muscle tissue development  positive regulation of skeletal muscle cell proliferation  myotube differentiation  morphogen activity  morphogen activity  intein-mediated protein splicing  spinal cord dorsal/ventral patterning  spinal cord motor neuron differentiation  thalamus development  dorsal/ventral neural tube patterning  cerebellar granule cell precursor proliferation  smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation  telencephalon regionalization  establishment of cell polarity  regulation of proteolysis  positive regulation of Wnt signaling pathway  lung development  embryonic limb morphogenesis  negative regulation of cell migration  male genitalia development  prostate gland development  thyroid gland development  forebrain development  midbrain development  hindbrain development  pancreas development  hair follicle morphogenesis  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  T cell differentiation in thymus  positive regulation of T cell differentiation in thymus  positive regulation of immature T cell proliferation in thymus  negative regulation of transcription elongation from RNA polymerase II promoter  protein localization to nucleus  embryonic forelimb morphogenesis  embryonic hindlimb morphogenesis  regulation of cell proliferation  negative regulation of T cell proliferation  positive regulation of protein import into nucleus  odontogenesis of dentin-containing tooth  regulation of odontogenesis  embryonic digit morphogenesis  camera-type eye development  negative regulation of apoptotic process  laminin-1 binding  CD4-positive or CD8-positive, alpha-beta T cell lineage commitment  positive thymic T cell selection  negative thymic T cell selection  intermediate filament organization  membrane raft  myoblast differentiation  negative regulation of cell differentiation  positive regulation of smoothened signaling pathway  positive regulation of smoothened signaling pathway  positive regulation of transcription, DNA-templated  positive regulation of transcription by RNA polymerase II  positive regulation of alpha-beta T cell differentiation  negative regulation of alpha-beta T cell differentiation  cell development  thymus development  embryonic digestive tract morphogenesis  embryonic foregut morphogenesis  positive regulation of skeletal muscle tissue development  animal organ formation  neuron fate commitment  embryonic skeletal system development  oligodendrocyte differentiation  positive regulation of oligodendrocyte differentiation  branching morphogenesis of an epithelial tube  inner ear development  formation of anatomical boundary  stem cell development  positive regulation of striated muscle cell differentiation  positive regulation of cell division  Bergmann glial cell differentiation  roof of mouth development  canonical Wnt signaling pathway  limb bud formation  lung epithelium development  trachea morphogenesis  branching involved in salivary gland morphogenesis  bud outgrowth involved in lung branching  right lung development  left lung development  lung lobe morphogenesis  lung-associated mesenchyme development  primary prostatic bud elongation  prostate epithelial cord elongation  salivary gland cavitation  epithelial cell proliferation involved in salivary gland morphogenesis  regulation of prostatic bud formation  epithelial-mesenchymal signaling involved in prostate gland development  positive regulation of epithelial cell proliferation involved in prostate gland development  regulation of mesenchymal cell proliferation involved in prostate gland development  mesenchymal smoothened signaling pathway involved in prostate gland development  artery development  mesenchymal cell proliferation involved in lung development  somite development  positive regulation of sclerotome development  collagen-containing extracellular matrix  cellular response to lithium ion  dopaminergic neuron differentiation  renal system development  metanephric mesenchymal cell proliferation involved in metanephros development  negative regulation of canonical Wnt signaling pathway  negative regulation of cholesterol efflux  apoptotic signaling pathway  regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry  regulation of protein localization to nucleus  negative regulation of dopaminergic neuron differentiation  tracheoesophageal septum formation  negative regulation of ureter smooth muscle cell differentiation  positive regulation of ureter smooth muscle cell differentiation  negative regulation of kidney smooth muscle cell differentiation  positive regulation of kidney smooth muscle cell differentiation  positive regulation of mesenchymal cell proliferation involved in ureter development  negative regulation of mesenchymal cell apoptotic process  
Ontology : EGO-EBInegative regulation of transcription by RNA polymerase II  branching involved in blood vessel morphogenesis  vasculogenesis  metanephros development  branching involved in ureteric bud morphogenesis  cell fate specification  cell fate specification  neural crest cell migration  heart looping  positive regulation of neuroblast proliferation  osteoblast development  lymphoid progenitor cell differentiation  determination of left/right asymmetry in lateral mesoderm  patched binding  patched binding  calcium ion binding  calcium ion binding  protein binding  glycosaminoglycan binding  extracellular region  extracellular space  extracellular space  extracellular space  endoplasmic reticulum lumen  cytosol  plasma membrane  endocytosis  smoothened signaling pathway  smoothened signaling pathway  smoothened signaling pathway  positive regulation of hh target transcription factor activity  cell-cell signaling  pattern specification process  ectoderm development  neuroblast proliferation  axon guidance  central nervous system development  ventral midline development  hindgut morphogenesis  heart development  blood coagulation  androgen metabolic process  peptidase activity  zinc ion binding  positive regulation of cell proliferation  positive regulation of cell proliferation  embryonic pattern specification  polarity specification of anterior/posterior axis  dorsal/ventral pattern formation  cell surface  regulation of gene expression  oligodendrocyte development  striated muscle tissue development  positive regulation of skeletal muscle cell proliferation  myotube differentiation  morphogen activity  morphogen activity  intein-mediated protein splicing  spinal cord dorsal/ventral patterning  spinal cord motor neuron differentiation  thalamus development  dorsal/ventral neural tube patterning  cerebellar granule cell precursor proliferation  smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation  telencephalon regionalization  establishment of cell polarity  regulation of proteolysis  positive regulation of Wnt signaling pathway  lung development  embryonic limb morphogenesis  negative regulation of cell migration  male genitalia development  prostate gland development  thyroid gland development  forebrain development  midbrain development  hindbrain development  pancreas development  hair follicle morphogenesis  negative regulation of proteasomal ubiquitin-dependent protein catabolic process  T cell differentiation in thymus  positive regulation of T cell differentiation in thymus  positive regulation of immature T cell proliferation in thymus  negative regulation of transcription elongation from RNA polymerase II promoter  protein localization to nucleus  embryonic forelimb morphogenesis  embryonic hindlimb morphogenesis  regulation of cell proliferation  negative regulation of T cell proliferation  positive regulation of protein import into nucleus  odontogenesis of dentin-containing tooth  regulation of odontogenesis  embryonic digit morphogenesis  camera-type eye development  negative regulation of apoptotic process  laminin-1 binding  CD4-positive or CD8-positive, alpha-beta T cell lineage commitment  positive thymic T cell selection  negative thymic T cell selection  intermediate filament organization  membrane raft  myoblast differentiation  negative regulation of cell differentiation  positive regulation of smoothened signaling pathway  positive regulation of smoothened signaling pathway  positive regulation of transcription, DNA-templated  positive regulation of transcription by RNA polymerase II  positive regulation of alpha-beta T cell differentiation  negative regulation of alpha-beta T cell differentiation  cell development  thymus development  embryonic digestive tract morphogenesis  embryonic foregut morphogenesis  positive regulation of skeletal muscle tissue development  animal organ formation  neuron fate commitment  embryonic skeletal system development  oligodendrocyte differentiation  positive regulation of oligodendrocyte differentiation  branching morphogenesis of an epithelial tube  inner ear development  formation of anatomical boundary  stem cell development  positive regulation of striated muscle cell differentiation  positive regulation of cell division  Bergmann glial cell differentiation  roof of mouth development  canonical Wnt signaling pathway  limb bud formation  lung epithelium development  trachea morphogenesis  branching involved in salivary gland morphogenesis  bud outgrowth involved in lung branching  right lung development  left lung development  lung lobe morphogenesis  lung-associated mesenchyme development  primary prostatic bud elongation  prostate epithelial cord elongation  salivary gland cavitation  epithelial cell proliferation involved in salivary gland morphogenesis  regulation of prostatic bud formation  epithelial-mesenchymal signaling involved in prostate gland development  positive regulation of epithelial cell proliferation involved in prostate gland development  regulation of mesenchymal cell proliferation involved in prostate gland development  mesenchymal smoothened signaling pathway involved in prostate gland development  artery development  mesenchymal cell proliferation involved in lung development  somite development  positive regulation of sclerotome development  collagen-containing extracellular matrix  cellular response to lithium ion  dopaminergic neuron differentiation  renal system development  metanephric mesenchymal cell proliferation involved in metanephros development  negative regulation of canonical Wnt signaling pathway  negative regulation of cholesterol efflux  apoptotic signaling pathway  regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry  regulation of protein localization to nucleus  negative regulation of dopaminergic neuron differentiation  tracheoesophageal septum formation  negative regulation of ureter smooth muscle cell differentiation  positive regulation of ureter smooth muscle cell differentiation  negative regulation of kidney smooth muscle cell differentiation  positive regulation of kidney smooth muscle cell differentiation  positive regulation of mesenchymal cell proliferation involved in ureter development  negative regulation of mesenchymal cell apoptotic process  
Pathways : KEGGHedgehog signaling pathway    Pathways in cancer    Basal cell carcinoma   
REACTOMEQ15465 [protein]
REACTOME PathwaysR-HSA-5658034 [pathway]   
NDEx NetworkSHH
Atlas of Cancer Signalling NetworkSHH
Wikipedia pathwaysSHH
Orthology - Evolution
OrthoDB6469
GeneTree (enSembl)ENSG00000164690
Phylogenetic Trees/Animal Genes : TreeFamSHH
HOGENOMQ15465
Homologs : HomoloGeneSHH
Homology/Alignments : Family Browser (UCSC)SHH
Gene fusions - Rearrangements
Fusion : MitelmanDNAJB6/SHH [7q36.3/7q36.3]  [t(7;7)(q36;q36)]  
Fusion : FusionGDB33780    33781    33782   
Fusion : Fusion_HubSHH--GLI    SHH--MBS    SHH--PLCB1    SHH--PTCH    SHH--RALGDS    SHH--TSPAN14   
Fusion : QuiverSHH
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSHH [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SHH
dbVarSHH
ClinVarSHH
1000_GenomesSHH 
Exome Variant ServerSHH
ExAC (Exome Aggregation Consortium)ENSG00000164690
GNOMAD BrowserENSG00000164690
Varsome BrowserSHH
Genetic variants : HAPMAP6469
Genomic Variants (DGV)SHH [DGVbeta]
DECIPHERSHH [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSHH 
Mutations
ICGC Data PortalSHH 
TCGA Data PortalSHH 
Broad Tumor PortalSHH
OASIS PortalSHH [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSHH  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DSHH
Mutations and Diseases : HGMDSHH
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SHH
DgiDB (Drug Gene Interaction Database)SHH
DoCM (Curated mutations)SHH (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SHH (select a term)
intoGenSHH
NCG5 (London)SHH
Cancer3DSHH(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM142945    147250    269160    600725    611638   
Orphanet580    2153    2662    2956    20436    20435    18904    20983    20982    21021    21022    12327    12486    12484    12485    13955   
DisGeNETSHH
MedgenSHH
Genetic Testing Registry SHH
NextProtQ15465 [Medical]
TSGene6469
GENETestsSHH
Target ValidationSHH
Huge Navigator SHH [HugePedia]
snp3D : Map Gene to Disease6469
BioCentury BCIQSHH
ClinGenSHH (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6469
Chemical/Pharm GKB GenePA35752
Clinical trialSHH
Miscellaneous
canSAR (ICR)SHH (select the gene name)
DataMed IndexSHH
Other databasehttp://www.molgen.mpg.de/research/mundlos/projects_dsh.html
Other databasehttp://anatomy.med.unsw.edu.au/cbl/embryo/
Other databasehttp://www.evol.nw.ru/labs/lab38/spirov/hox_pro/shh.html
Other databasehttp://www.devbio.com/chap06/link0603.shtml
Probes
Litterature
PubMed485 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSHH
EVEXSHH
GoPubMedSHH
iHOPSHH
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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