SHH

Summary

SHH (sonic hedgehog signaling molecule, HGNC:10848) is a protein-coding gene on chromosome 7q36.3, encoding Sonic hedgehog protein (Q15465). The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 6469 — RefSeq curated summary.

At a glance

• Gene–disease (curated): holoprosencephaly 3 (Definitive, GenCC) — +10 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 503 total — 62 pathogenic, 61 likely-pathogenic
• Phenotypes (HPO): 162
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000193

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10848
Approved symbol	SHH
Name	sonic hedgehog signaling molecule
Location	7q36.3
Locus type	gene with protein product
Status	Approved
Aliases	HHG1, SMMCI, TPT, TPTPS, MCOPCB5
Ensembl gene	ENSG00000164690
Ensembl biotype	protein_coding
OMIM	600725
Entrez	6469

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000297261, ENST00000430104, ENST00000435425, ENST00000441114, ENST00000472308

RefSeq mRNA: 2 — MANE Select: NM_000193 NM_000193, NM_001310462

CCDS: CCDS5942

Canonical transcript exons

ENST00000297261 — 3 exons

Exon	Start	End
ENSE00001086614	155811823	155812463
ENSE00001086617	155806296	155806557
ENSE00001149618	155799980	155803726

Expression profiles

Bgee: expression breadth ubiquitous, 131 present calls, max score 85.69.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8044 / max 273.5215, expressed in 428 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87048	1.5417	395
87046	0.0893	46
87047	0.0709	32
87045	0.0516	26
205018	0.0509	25

Top tissues by expression

243 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	85.69	gold quality
right lobe of liver	UBERON:0001114	85.66	gold quality
epithelial cell of pancreas	CL:0000083	84.05	silver quality
sural nerve	UBERON:0015488	83.93	gold quality
tibial nerve	UBERON:0001323	80.65	gold quality
right adrenal gland cortex	UBERON:0035827	80.14	gold quality
liver	UBERON:0002107	79.21	gold quality
right adrenal gland	UBERON:0001233	79.01	gold quality
left adrenal gland cortex	UBERON:0035825	77.97	gold quality
adrenal cortex	UBERON:0001235	77.82	gold quality
left adrenal gland	UBERON:0001234	77.08	gold quality
adrenal gland	UBERON:0002369	75.04	gold quality
metanephros cortex	UBERON:0010533	74.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.91	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	73.78	gold quality
mucosa of transverse colon	UBERON:0004991	72.81	gold quality
sperm	CL:0000019	72.72	gold quality
gall bladder	UBERON:0002110	72.65	gold quality
urinary bladder	UBERON:0001255	72.46	gold quality
tibialis anterior	UBERON:0001385	71.97	silver quality
kidney epithelium	UBERON:0004819	70.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	70.78	gold quality
metanephros	UBERON:0000081	70.60	gold quality
dorsal root ganglion	UBERON:0000044	70.27	gold quality
upper arm skin	UBERON:0004263	70.20	gold quality
deltoid	UBERON:0001476	69.77	gold quality
adult mammalian kidney	UBERON:0000082	69.02	gold quality
mucosa of sigmoid colon	UBERON:0004993	68.49	silver quality
body of stomach	UBERON:0001161	68.39	gold quality
colonic mucosa	UBERON:0000317	67.93	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1295.18
E-ANND-3	yes	12.71
E-MTAB-6142	no	1.10

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
CCND1	Activation
FGF4	Repression
HHIP	Activation
KRT73	Repression
NKX2-2	Activation
NKX6-1	Activation
PVR	Activation
SOSTDC1	Activation
SP5	Repression

Upstream regulators (CollecTRI, top): ARX, BMP2, CDX2, CTNNB1, ETV4, ETV5, FOXA1, FOXA2, GATA6, GLI1, GLI3, HAND1, HAND2, HNF1B, HOXD11, HOXD12, IRX1, ISL1, KLF5, LEF1, MEIS3, MSX1, MTF2, MYF5, NFKB, NFKBIA, NHLH1, NKX2-2, NR2E1, NR2F2, NR5A1, OLIG1, OLIG2, OTX2, PAX3, PAX6, PAX9, PITX1, POU4F2, RARA

miRNA regulators (miRDB)

53 targeting SHH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-6878-3P	99.24	64.23	920

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• While the gene contributes to face development, it is not a frequent cause of cleft lip or palate. (PMID:11857543)
• role in activating poliovirus receptor/CD155 gene (PMID:11983699)
• characterization of (SHH) expression in the human fetal prostate (PMID:12394760)
• Shh-mediated signaling is a physiological component of T cell responses, which acts to modulate CD4+ T cell effector function. (PMID:12421920)
• REVIEW: Hedgehog signaling in human disease (PMID:12495844)
• induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase (PMID:12514186)
• The Tbx1 regulatory region was responsive to signaling by Sonic hedgehog (Shh) in vivo. (PMID:12533514)
• Down-reuglation of this protein’s expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia. (PMID:12547712)
• Role for hedgehog signaling in regeneration and carcinogenesis of airway epithelium (PMID:12629553)
• Aberrant Shh signaling may play a critical role in the pathogenesis of esophageal atresia with tracheoesophageal fistula in humans. (PMID:12632368)
• These studies are the first demonstration that mutations in SHH associated with human HPE (holoprosencephaly) perturb the in vivo patterning function of SHH in the developing nervous system. (PMID:12709790)
• deregulated hedgehog signaling in the genesis of basaloid follicular hamartomas (PMID:12773389)
• Adriamycin influences the Shh signalling pathway, resulting in disruption of normal development of the foregut. (PMID:12783258)
• mutations in a long-range Shh enhancer located in an intron of the limb region 1 gene result in preaxial polydactyly (PMID:12837695)
• model of the interactions between beta-catenin and hedgehog signaling in the epidermis in which SHH promotes proliferation of progenitors of the hair lineages whereas IHH stimulates proliferation of sebocyte precursors (PMID:12917489)
• In gray matter from brains of multiple sclerosis (MS) victims, the total amount of Shh was less than normals and the signaling 20 kDa protein was greatly reduced. (PMID:12926841)
• a wide range of digestive tract tumours, including most of those originating in the oesophagus, stomach, biliary tract and pancreas, but not in the colon, display increased Hh pathway activity, which is suppressible by cyclopamine, a Hh pathway antagonist (PMID:14520411)
• Hedgehog pathway may have an early and critical role in the genesis of pancreatic cancer; maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis (PMID:14520413)
• Decreased expression of the Shh pathway in atrophic gastritis and gastric cancer might reflect altered differentiation processes within the gastric unit and contributes to the development of gastric atrophy. (PMID:14691301)
• Shh signaling has a role in the cellular proliferation of oral squamous cell carcinoma cells (PMID:14733907)
• signaling molecules might play a role in epithelial-mesenchymal interactions and cell proliferation in tooth development as well as in growth of [ameloblastomas] (PMID:15128061)
• SHH signalling can increase aberrant cell survival in colorectal tumour cells. (PMID:15170664)
• Thirteen novel SHH mutations found in a cohort of Holoprosencephaly patinets. (PMID:15221788)
• Overexpression of a wild-type regulatory subunit of protein kinase A is sufficient to activate sonic hedgehog target gene transcription. (PMID:15238528)
• Results identify REN(KCTD11) as a suppressor of Hedgehog signaling and suggest that its inactivation might lead to a deregulation of the tumor-promoting Hedgehog pathway in medulloblastoma. (PMID:15249678)
• sonic hedgehog mutations have a role in holoprosencephaly (PMID:15292211)
• Data report expression of sonic hedgehog-GLI-1 pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. (PMID:15314219)
• Shh down-regulated in the precursor cell population the expression of IL-7R as well as stromal-derived factor-1 chemokine receptor, CXCR4, and inhibited IL-7-dependent STAT5 phosphorylation. (PMID:15470048)
• SHH signaling in inflammatory diseases of the gut acts to ensure stem cell restitution of damaged mucosal epithelium. (PMID:15502857)
• Taken together, our data suggest that the hedgehog pathway is weakly active in normal adult urothelial cells and of limited importance in transitional cell carcinoma. (PMID:15521068)
• ptc1 mutation enhances a downstream reporter of sonic hedgehog (shh)-ptc1 signaling. (PMID:15592520)
• an intact EGF signaling axis cooperates with shh and is a critical mediator of matrix invasion in a tumor type characterized by disrupted shh. (PMID:15675968)
• Elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 99 primary gastric cancers. (PMID:15905200)
• regulatory elements around the SHH gene may contribute to the maintenance of conserved synteny across human chromosome 7q36.3 (PMID:15939571)
• elevated expression of Shh and its target genes is quite common in esophageal cancers (PMID:16003737)
• Shh might maintain pituitary cells in nonproliferative state. Shh is newly described hypophysiotropic cytokine and its down-regulation may be involved in pathogenesis of pituitary adenomas. (PMID:16159933)
• SHH gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia. (PMID:16244652)
• The effects of seven missense mutations associated with holoprosencephaly that affect the N-terminal signaling domain of SHH have been characterized (PMID:16282375)
• This review highlights the hypothesis of hedgehog pathway activation in damaged nerve tissue, inducing the repair process, as a potentially new approach to treatment of neurodegenerative diseases and dysfunction, including spinal cord injury. (PMID:16300466)
• Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage. (PMID:16322088)

Cross-species orthologs

23 orthologs

Organism	Symbol	Gene ID
danio_rerio	shhb	ENSDARG00000038867
danio_rerio	shha	ENSDARG00000068567
mus_musculus	Shh	ENSMUSG00000002633
rattus_norvegicus	Shh	ENSRNOG00000006120
caenorhabditis_elegans		WBGENE00001690
caenorhabditis_elegans		WBGENE00001691
caenorhabditis_elegans		WBGENE00001692
caenorhabditis_elegans		WBGENE00001693
caenorhabditis_elegans		WBGENE00001694
caenorhabditis_elegans		WBGENE00001695
caenorhabditis_elegans		WBGENE00001696
caenorhabditis_elegans		WBGENE00001697
caenorhabditis_elegans		WBGENE00001698
caenorhabditis_elegans		WBGENE00001699
caenorhabditis_elegans		WBGENE00001700
caenorhabditis_elegans		WBGENE00001702
caenorhabditis_elegans		WBGENE00001703
caenorhabditis_elegans		WBGENE00006949
caenorhabditis_elegans		WBGENE00006950
caenorhabditis_elegans		WBGENE00006951
caenorhabditis_elegans		WBGENE00006952
caenorhabditis_elegans		WBGENE00006953
caenorhabditis_elegans		WBGENE00006954

Paralogs (2): DHH (ENSG00000139549), IHH (ENSG00000163501)

Protein

Protein identifiers

Sonic hedgehog protein — Q15465 (reviewed: Q15465)

Alternative names: HHG-1, Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains

All UniProt accessions (4): C9JC48, Q15465, F8WB84, F8WEH4

UniProt curated annotations — full annotation on UniProt →

Function. The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein into two parts (ShhN and ShhC) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated ShhN. Both activities occur in the endoplasmic reticulum. Once cleaved, ShhC is degraded in the endoplasmic reticulum. The dually lipidated sonic hedgehog protein N-product (ShhNp) is a morphogen which is essential for a variety of patterning events during development. Induces ventral cell fate in the neural tube and somites. Involved in the patterning of the anterior-posterior axis of the developing limb bud. Essential for axon guidance. Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTCH1 represses the constitutive signaling activity of SMO.

Subunit / interactions. Multimer. Interacts with HHATL/GUP1 which negatively regulates HHAT-mediated palmitoylation of the SHH N-terminus. Interacts with BOC and CDON. Interacts with HHIP. Interacts with DISP1 via its cholesterol anchor. Interacts with SCUBE2. Interacts with glypican GPC3.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane. Secreted Cell membrane.

Post-translational modifications. The C-terminal domain displays an autoproteolysis activity and a cholesterol transferase activity. Both activities result in the cleavage of the full-length protein and covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-terminal fragment (ShhN). Cholesterylation is required for the sonic hedgehog protein N-product targeting to lipid rafts and multimerization. ShhN is the active species in both local and long-range signaling, whereas the C-product (ShhC) is degraded in the endoplasmic reticulum. N-palmitoylation by HHAT of ShhN is required for sonic hedgehog protein N-product multimerization and full activity. It is a prerequisite for the membrane-proximal positioning and the subsequent shedding of this N-terminal peptide. The lipidated N- and C-terminal peptides of ShhNp can be cleaved (shedding). The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub (CW) motif site. The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2.

Disease relevance. Microphthalmia/Coloboma 5 (MCOPCB5) [MIM:611638] A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). The disease is caused by variants affecting the gene represented in this entry. Holoprosencephaly 3 (HPE3) [MIM:142945] A form of holoprosencephaly, a structural anomaly of the brain in which the developing forebrain fails to correctly separate into right and left hemispheres. It is a genetically and clinically heterogeneous disorder with a wide spectrum of severity, ranging from alobar holoprosencephaly with severe facial abnormalities, such as cyclopia and proboscis, to mild forms that include lobar or microform holoprosencephaly, without cerebral malformations and with mild craniofacial defects. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. The disease is caused by variants affecting the gene represented in this entry. Solitary median maxillary central incisor (SMMCI) [MIM:147250] Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. The disease is caused by variants affecting the gene represented in this entry. Triphalangeal thumb with polysyndactyly (TPTPS) [MIM:190605] Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. The gene represented in this entry is involved in disease pathogenesis. SHH expression is altered due to disease-causing variants located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH. Preaxial polydactyly 2 (PPD2) [MIM:174500] Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences. Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740] An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences. Laurin-Sandrow syndrome (LSS) [MIM:135750] A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5.

Domain organisation. Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain. The Cardin-Weintraub (CW) motif is required for heparan sulfate binding of the solubilized ShhNp. The N-terminal palmitoylated peptide is cleaved at the heparan sulfate-binding Cardin-Weintraub (CW) motif site. The cleavage reduced the interactions with heparan sulfate. The cleavage is enhanced by SCUBE2.

Similarity. Belongs to the hedgehog family.

RefSeq proteins (2): NP_000184, NP_001297391 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000320	Hedgehog_signalling_dom	Domain
IPR001657	Hedgehog	Family
IPR001767	Hedgehog_Hint	Domain
IPR003586	Hint_dom_C	Domain
IPR003587	Hint_dom_N	Domain
IPR006141	Intein_N	PTM
IPR009045	Zn_M74/Hedgehog-like	Homologous_superfamily
IPR036844	Hint_dom_sf	Homologous_superfamily
IPR050387	Hedgehog_Signaling	Family

Pfam: PF01079, PF01085

Catalyzed reactions (Rhea), 1 shown:

• glycyl-L-cysteinyl-[protein] + cholesterol + H(+) = [protein]-C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl-[protein] (RHEA:59504)

UniProt features (138 total): sequence variant 94, binding site 12, strand 8, helix 7, site 4, chain 2, lipid moiety-binding region 2, region of interest 2, compositionally biased region 2, signal peptide 1, mutagenesis site 1, turn 1, glycosylation site 1, short sequence motif 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
6PJV	X-RAY DIFFRACTION	1.43
8Z3A	X-RAY DIFFRACTION	1.75
8Z39	X-RAY DIFFRACTION	1.8
3MXW	X-RAY DIFFRACTION	1.83
3M1N	X-RAY DIFFRACTION	1.85
8Z2V	X-RAY DIFFRACTION	1.89
8YYZ	X-RAY DIFFRACTION	1.9
7URF	ELECTRON MICROSCOPY	2.8
3HO5	X-RAY DIFFRACTION	3.01
7MHZ	ELECTRON MICROSCOPY	3.2
6RMG	ELECTRON MICROSCOPY	3.4
6E1H	ELECTRON MICROSCOPY	3.5
6RVD	ELECTRON MICROSCOPY	3.5
7RHQ	ELECTRON MICROSCOPY	3.53
6DMY	ELECTRON MICROSCOPY	3.6
6N7H	ELECTRON MICROSCOPY	3.6
6OEV	ELECTRON MICROSCOPY	3.8
7E2I	ELECTRON MICROSCOPY	4.07
6N7K	ELECTRON MICROSCOPY	6.5
6N7G	ELECTRON MICROSCOPY	6.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15465-F1	80.23	0.50

Antibody-complex structures (SAbDab): 7 — 3MXW, 7MHZ, 7URF, 8YYZ, 8Z2V, 8Z39, 8Z3A

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 197–198 (cleavage; by autolysis); 243 (involved in cholesterol transfer); 267 (involved in auto-cleavage); 270 (essential for auto-cleavage)

Ligand- & substrate-binding residues (12): 90; 95; 125; 126; 126; 129; 131; 140; 147; 182; 89; 90

Post-translational modifications (2): 24, 197

Glycosylation sites (1): 278

Mutagenesis-validated functional residues (1):

Position	Phenotype
24	abolishes palmitoylation.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-5362798	Release of Hh-Np from the secreting cell
R-HSA-5632681	Ligand-receptor interactions
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5635838	Activation of SMO
R-HSA-5658034	HHAT G278V doesn’t palmitoylate Hh-Np
R-HSA-9758920	Formation of lateral plate mesoderm
R-HSA-9796292	Formation of axial mesoderm
R-HSA-9937080	Developmental Lineage of Multipotent Pancreatic Progenitor Cells
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-372790	Signaling by GPCR
R-HSA-500792	GPCR ligand binding
R-HSA-5358351	Signaling by Hedgehog
R-HSA-5387390	Hh mutants abrogate ligand secretion
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-9734767	Developmental Cell Lineages
R-HSA-9758941	Gastrulation
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells

MSigDB gene sets: 951 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_URETER_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (205): negative regulation of transcription by RNA polymerase II (GO:0000122), branching involved in blood vessel morphogenesis (GO:0001569), vasculogenesis (GO:0001570), metanephros development (GO:0001656), branching involved in ureteric bud morphogenesis (GO:0001658), cell fate specification (GO:0001708), neural crest cell migration (GO:0001755), heart looping (GO:0001947), positive regulation of neuroblast proliferation (GO:0002052), osteoblast development (GO:0002076), lymphoid progenitor cell differentiation (GO:0002320), determination of left/right asymmetry in lateral mesoderm (GO:0003140), protein import into nucleus (GO:0006606), endocytosis (GO:0006897), smoothened signaling pathway (GO:0007224), cell-cell signaling (GO:0007267), pattern specification process (GO:0007389), ectoderm development (GO:0007398), neuroblast proliferation (GO:0007405), axon guidance (GO:0007411), central nervous system development (GO:0007417), ventral midline development (GO:0007418), hindgut morphogenesis (GO:0007442), heart development (GO:0007507), blood coagulation (GO:0007596), androgen metabolic process (GO:0008209), positive regulation of cell population proliferation (GO:0008284), embryonic pattern specification (GO:0009880), polarity specification of anterior/posterior axis (GO:0009949), dorsal/ventral pattern formation (GO:0009953), regulation of gene expression (GO:0010468), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), oligodendrocyte development (GO:0014003), skeletal muscle cell proliferation (GO:0014856), positive regulation of skeletal muscle cell proliferation (GO:0014858), intein-mediated protein splicing (GO:0016539), protein autoprocessing (GO:0016540), spinal cord dorsal/ventral patterning (GO:0021513), spinal cord motor neuron differentiation (GO:0021522)

GO Molecular Function (13): endopeptidase activity (GO:0004175), patched binding (GO:0005113), calcium ion binding (GO:0005509), glycosaminoglycan binding (GO:0005539), peptidase activity (GO:0008233), zinc ion binding (GO:0008270), morphogen activity (GO:0016015), laminin-1 binding (GO:0043237), cholesterol-protein transferase activity (GO:0140853), protein binding (GO:0005515), transferase activity (GO:0016740), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (13): Golgi membrane (GO:0000139), extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), extracellular matrix (GO:0031012), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Signaling by Hedgehog	2
Hh mutants abrogate ligand secretion	2
Hedgehog ‘on’ state	2
Gastrulation	2
Signal Transduction	2
GPCR ligand binding	1
Hedgehog ligand biogenesis	1
Developmental Cell Lineages of the Exocrine Pancreas	1
Signaling by GPCR	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
blood vessel morphogenesis	2
branching morphogenesis of an epithelial tube	2
catalytic activity, acting on a protein	2
catalytic activity	2
endomembrane system	2
intracellular membrane-bounded organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
angiogenesis	1
cell differentiation	1
kidney development	1
ureteric bud morphogenesis	1
cell fate commitment	1
cellular developmental process	1
neural crest cell development	1
mesenchymal cell migration	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
osteoblast differentiation	1
cell development	1
hematopoietic progenitor cell differentiation	1
determination of left/right symmetry	1
lateral mesoderm development	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
cell surface receptor signaling pathway	1
cell communication	1

Protein interactions and networks

STRING

4911 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHH	SMO	Q99835	999
SHH	PTCH1	Q13635	999
SHH	PTCH2	Q9Y6C5	996
SHH	GAS1	P54826	992
SHH	HHIP	Q96QV1	986
SHH	CDON	Q4KMG0	978
SHH	GLI1	P08151	976
SHH	GLI2	P10070	973
SHH	GLI3	P10071	963
SHH	FGF8	P55075	954
SHH	BOC	Q9BWV1	936
SHH	NOG	Q13253	935
SHH	SUFU	Q9UMX1	934
SHH	FGF4	P08620	927
SHH	LRP2	P98164	925

IntAct

28 interactions, top by confidence:

A	B	Type	Score
PTCH1	SHH	psi-mi:“MI:0407”(direct interaction)	0.780
SHH	PTCH1	psi-mi:“MI:0407”(direct interaction)	0.780
HHIP	SHH	psi-mi:“MI:0407”(direct interaction)	0.690
SHH	HHIP	psi-mi:“MI:0407”(direct interaction)	0.690
HHIP	SHH	psi-mi:“MI:0915”(physical association)	0.690
	SHH	psi-mi:“MI:0407”(direct interaction)	0.440
SHH	PTCH1	psi-mi:“MI:0407”(direct interaction)	0.440
HHIP	PTCH1	psi-mi:“MI:0915”(physical association)	0.400
HHIP	DHH	psi-mi:“MI:0915”(physical association)	0.400
HHIP	IHH	psi-mi:“MI:0915”(physical association)	0.400
PTCH1	SHH	psi-mi:“MI:0915”(physical association)	0.400
EGFR	SHH	psi-mi:“MI:2364”(proximity)	0.270
SHH	PTEN	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (14): EDEM1 (Affinity Capture-Western), EDEM2 (Affinity Capture-Western), EDEM3 (Affinity Capture-Western), SHH (Affinity Capture-Western), PTCH1 (Co-localization), SHH (Co-purification), SHH (Affinity Capture-Western), PTCH1 (Reconstituted Complex), GSX2 (Affinity Capture-Western), SHH (Affinity Capture-Western), SHH (Affinity Capture-Western), DERL1 (Affinity Capture-Western), DERL2 (Affinity Capture-Western), SHH (Affinity Capture-Western)

ESM2 similar proteins: A1A4M2, A4IFG4, A5D8P8, A6NKD9, A7E2M3, B4F7F3, E9Q6B2, F1MX48, F1SAM7, O97676, P18065, P36956, P47877, P49705, P56720, P56873, Q00709, Q00973, Q09200, Q0IHY5, Q15465, Q24JP5, Q2YD98, Q3TAS6, Q58CS8, Q5QQ49, Q5UCC4, Q60416, Q60698, Q641Q3, Q68FE7, Q6AYH6, Q6DVA0, Q6P7K5, Q6UKI2, Q6WVG3, Q80WF4, Q8IW70, Q8JGM4, Q8K064

Diamond homologs: B3LV44, B3P7F8, B4G2I8, B4HFB7, B4JTF5, B4K4M0, B4LZT9, B4NJP3, B4PN49, B4R1D8, O13215, O13220, O13226, O13234, O13235, O13238, O13240, O13241, O13243, O13247, O13250, O13253, O43323, P56674, P79682, P79691, P79693, P79696, P79709, P79711, P79712, P79715, P79717, P79719, P79729, P79838, P79839, P79850, P79852, P79853

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
SHH	down-regulates	CP	binding
SHH	“down-regulates activity”	PTCH1	binding
HHAT	up-regulates	SHH	palmitoylation
EXTL1	down-regulates	SHH	binding
CDO1	up-regulates	SHH	binding
SHH	“up-regulates activity”	GLI2
SHH	up-regulates	AKT1
N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide	down-regulates	SHH	“chemical inhibition”
SHH	up-regulates	MYF5
SHH	up-regulates	MYOD1
BMP2	“down-regulates quantity by repression”	SHH	“transcriptional regulation”
DISP1	“up-regulates activity”	SHH	binding
SHH	“down-regulates activity”	PTCH2	binding
SHH	up-regulates	AKT
GPC6	“up-regulates activity”	SHH	binding
SHH	“up-regulates activity”	SMO
RORA	“up-regulates quantity by expression”	SHH	“transcriptional regulation”
SLITRK5	“down-regulates activity”	SHH	binding
HHIP	“down-regulates activity”	SHH	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

503 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	61
Uncertain significance	221
Likely benign	106
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1164032	NM_000193.4(SHH):c.*2824C>A	Pathogenic
1176253	NM_000193.4(SHH):c.525C>G (p.Tyr175Ter)	Pathogenic
1458762	NC_000007.13:g.(?155596114)(155657138_?)del	Pathogenic
1693157	NM_000193.4(SHH):c.562+1G>A	Pathogenic
1807779	GRCh37/hg19 7q36.3(chr7:155576627-155607157)x1	Pathogenic
2577434	NM_000193.4(SHH):c.705del (p.Leu234_Tyr235insTer)	Pathogenic
2582290	NM_000193.4(SHH):c.1215_1217delinsA (p.Asp405fs)	Pathogenic
2582291	NM_000193.4(SHH):c.1302G>A (p.Trp434Ter)	Pathogenic
2671957	NM_000193.4(SHH):c.44C>A (p.Ser15Ter)	Pathogenic
3254599	NM_000193.4(SHH):c.136C>T (p.Gln46Ter)	Pathogenic
3340406	NM_000193.4(SHH):c.839C>A (p.Ser280Ter)	Pathogenic
3345617	NM_000193.4(SHH):c.1040C>A (p.Pro347Gln)	Pathogenic
3358962	NM_000193.4(SHH):c.37del (p.Val13fs)	Pathogenic
3384113	NM_000193.4(SHH):c.1308del (p.Gln437fs)	Pathogenic
374270	NM_000193.4(SHH):c.1284del (p.Thr429fs)	Pathogenic
3775118	NM_000193.4(SHH):c.72C>A (p.Cys24Ter)	Pathogenic
3775119	NM_000193.4(SHH):c.57C>A (p.Cys19Ter)	Pathogenic
3775129	NM_000193.4(SHH):c.388G>T (p.Glu130Ter)	Pathogenic
3775130	NM_000193.4(SHH):c.469A>T (p.Lys157Ter)	Pathogenic
3775131	NM_000193.4(SHH):c.211del (p.Glu71fs)	Pathogenic
3775132	NM_000193.4(SHH):c.87del (p.Phe30fs)	Pathogenic
3775138	NM_000193.4(SHH):c.404C>G (p.Ser135Ter)	Pathogenic
3775143	NM_000193.4(SHH):c.730del (p.Arg244fs)	Pathogenic
3775146	NM_000193.4(SHH):c.1015G>T (p.Glu339Ter)	Pathogenic
3775147	NM_000193.4(SHH):c.281_282dup (p.Asp95fs)	Pathogenic
3775148	NM_000193.4(SHH):c.1085C>A (p.Ser362Ter)	Pathogenic
3775149	NM_000193.4(SHH):c.587del (p.Gly196fs)	Pathogenic
3775159	NM_000193.4(SHH):c.121_122del (p.Pro41fs)	Pathogenic
379347	NM_000193.4(SHH):c.423C>A (p.Tyr141Ter)	Pathogenic
395377	GRCh37/hg19 7q36.3(chr7:155594374-156069411)x1	Pathogenic

SpliceAI

1028 predictions. Top by Δscore:

Variant	Effect	Δscore
7:155806290:GCTTA:G	donor_loss	1.0000
7:155806291:CTTA:C	donor_loss	1.0000
7:155806292:TTAC:T	donor_loss	1.0000
7:155806293:TAC:T	donor_loss	1.0000
7:155806294:A:AT	donor_loss	1.0000
7:155806295:C:A	donor_loss	1.0000
7:155806295:CCTG:C	donor_gain	1.0000
7:155802911:TG:T	donor_gain	0.9900
7:155803727:C:CC	acceptor_gain	0.9900
7:155806294:A:AC	donor_gain	0.9900
7:155806295:C:CC	donor_gain	0.9900
7:155806553:CACCT:C	acceptor_gain	0.9900
7:155811817:TCCTA:T	donor_loss	0.9900
7:155811818:CCTA:C	donor_loss	0.9900
7:155811819:CTACC:C	donor_loss	0.9900
7:155811820:TA:T	donor_loss	0.9900
7:155811821:A:AG	donor_loss	0.9900
7:155811822:CCT:C	donor_loss	0.9900
7:155803733:G:GC	acceptor_gain	0.9800
7:155806555:CCT:C	acceptor_gain	0.9800
7:155806556:CT:C	acceptor_gain	0.9800
7:155806556:CTC:C	acceptor_gain	0.9800
7:155806557:TCTG:T	acceptor_loss	0.9800
7:155806557:TCTGC:T	acceptor_gain	0.9800
7:155806558:C:A	acceptor_gain	0.9800
7:155806558:C:CC	acceptor_gain	0.9800
7:155806559:T:A	acceptor_loss	0.9800
7:155806775:T:TA	donor_gain	0.9800
7:155803724:TCT:T	acceptor_gain	0.9700
7:155803725:CT:C	acceptor_gain	0.9700

AlphaMissense

2947 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:155806300:T:A	K186N	1.000
7:155806300:T:G	K186N	1.000
7:155806304:A:T	V185E	1.000
7:155806307:G:A	S184L	1.000
7:155806307:G:C	S184W	1.000
7:155806308:A:G	S184P	1.000
7:155806309:G:C	C183W	1.000
7:155806310:C:T	C183Y	1.000
7:155806311:A:G	C183R	1.000
7:155806312:G:C	H182Q	1.000
7:155806312:G:T	H182Q	1.000
7:155806314:G:C	H182D	1.000
7:155806314:G:T	H182N	1.000
7:155806316:A:T	I181N	1.000
7:155806318:A:C	H180Q	1.000
7:155806318:A:T	H180Q	1.000
7:155806320:G:C	H180D	1.000
7:155806329:A:G	S177P	1.000
7:155806340:A:T	V173E	1.000
7:155806342:C:A	W172C	1.000
7:155806342:C:G	W172C	1.000
7:155806343:C:A	W172L	1.000
7:155806343:C:G	W172S	1.000
7:155806344:A:G	W172R	1.000
7:155806344:A:T	W172R	1.000
7:155806346:T:A	D171V	1.000
7:155806348:G:C	F170L	1.000
7:155806348:G:T	F170L	1.000
7:155806349:A:G	F170S	1.000
7:155806350:A:G	F170L	1.000

dbSNP variants (sampled 300 via entrez): RS1000058340 (7:155810099 C>A), RS1000106968 (7:155809965 G>A), RS1000111635 (7:155809417 C>A,T), RS1000294329 (7:155803910 C>T), RS1001478941 (7:155800268 T>C), RS1001700118 (7:155800208 G>C), RS1001753770 (7:155799937 T>A,C), RS1002234489 (7:155805228 C>A,T), RS1002294865 (7:155805701 C>T), RS1002346800 (7:155811265 C>T), RS1002691809 (7:155805002 G>A,C,T), RS1002712717 (7:155801406 A>G), RS1002753619 (7:155803000 G>A,C), RS1002755564 (7:155805487 A>C), RS1003018141 (7:155813986 G>A,T)

Disease associations

OMIM: gene MIM:600725 | disease phenotypes: MIM:142945, MIM:147250, MIM:269160, MIM:611638, MIM:182230, MIM:209850, MIM:200990, MIM:236100, MIM:613721, MIM:617755

GenCC curated gene-disease

Disease	Classification	Inheritance
holoprosencephaly 3	Definitive	Autosomal dominant
solitary median maxillary central incisor syndrome	Definitive	Autosomal dominant
polydactyly of a triphalangeal thumb	Definitive	Autosomal dominant
microphthalmia, isolated, with coloboma 5	Definitive	Autosomal dominant
skeletal system disorder	Moderate	Autosomal dominant
holoprosencephaly	Supportive	Autosomal recessive
triphalangeal thumb-polysyndactyly syndrome	Supportive	Autosomal dominant
hypoplastic tibiae-postaxial polydactyly syndrome	Supportive	Autosomal dominant
autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome	Supportive	Autosomal dominant
syndactyly type 4	Supportive	Autosomal dominant
microphthalmia, isolated, with coloboma	Supportive	Autosomal dominant

Mondo (19): holoprosencephaly 3 (MONDO:0007733), anemia (MONDO:0002280), solitary median maxillary central incisor syndrome (MONDO:0007819), schizencephaly (MONDO:0010011), microphthalmia, isolated, with coloboma 5 (MONDO:0012709), septooptic dysplasia (MONDO:0008428), autism (MONDO:0005260), obesity disorder (MONDO:0011122), acrocallosal syndrome (MONDO:0008708), holoprosencephaly (MONDO:0016296), developmental and epileptic encephalopathy, 11 (MONDO:0013388), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596), skeletal system disorder (MONDO:0005172), triphalangeal thumb-polysyndactyly syndrome (MONDO:0017454), (MONDO:0018052)

Orphanet (10): Holoprosencephaly (Orphanet:2162), Schizencephaly (Orphanet:799), Colobomatous microphthalmia (Orphanet:98938), Septo-optic dysplasia spectrum (Orphanet:3157), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Acrocallosal syndrome (Orphanet:36), Early infantile developmental and epileptic encephalopathy (Orphanet:1934), BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482), OBSOLETE: Solitary median maxillary central incisor syndrome (Orphanet:2286), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

162 total (30 of 162 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000062	Ambiguous genitalia
HP:0000104	Renal agenesis
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000322	Short philtrum
HP:0000366	Abnormality of the nose
HP:0000407	Sensorineural hearing impairment
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000458	Anosmia
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000504	Abnormality of vision
HP:0000520	Proptosis
HP:0000528	Anophthalmia
HP:0000567	Chorioretinal coloboma
HP:0000568	Microphthalmia

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000693_13	Platelet aggregation	8.000000e-08
GCST001819_1	Corneal astigmatism	8.000000e-07
GCST005985_27	Creatinine levels	2.000000e-08
GCST006976_112	Macular thickness	8.000000e-12
GCST007344_105	Estimated glomerular filtration rate	4.000000e-06
GCST007344_11	Estimated glomerular filtration rate	7.000000e-13
GCST007876_90	Estimated glomerular filtration rate	2.000000e-16
GCST008058_76	Estimated glomerular filtration rate	1.000000e-23
GCST008059_74	Estimated glomerular filtration rate	1.000000e-21
GCST008171_20	Platelet aggregation	1.000000e-06
GCST008745_67	Estimated glomerular filtration rate in non-diabetics	2.000000e-11
GCST008747_164	Estimated glomerular filtration rate	8.000000e-09
GCST008747_23	Estimated glomerular filtration rate	4.000000e-06
GCST010796_3497	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D055673	Acrocallosal Syndrome	C10.500.034.500; C16.131.666.034.500
D000740	Anemia	C15.378.050
D001321	Autistic Disorder	F03.625.164.113.500
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D065707	Schizencephaly	C10.500.507.500.750; C16.131.666.507.500.750
D025962	Septo-Optic Dysplasia	C10.292.562.700.375.875; C10.500.034.937; C10.500.760.500; C11.590.436.400.875; C16.131.666.034.937; C16.131.666.763.500
C564181	Holoprosencephaly 3 (supp.)
C537463	Microphthalmia associated with colobomatous cyst (supp.)
C566899	Microphthalmia, Isolated, with Coloboma 5 (supp.)
C537342	Single upper central incisor (supp.)
C566092	Syndactyly, Type IV (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5602 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 6,714 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL473417	VISMODEGIB	4	6,714

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

20 potent at pChembl≥5 of 24 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.82	IC50	15	nM	VISMODEGIB
7.00	IC50	100	nM	CHEMBL480889
6.77	Kd	170	nM	CHEMBL5276737
6.30	IC50	500	nM	JERVINE
6.26	Kd	550	nM	CHEMBL5185285
6.24	Kd	570	nM	CHEMBL1081556
6.22	IC50	600	nM	CYCLOPAMINE
5.76	IC50	1750	nM	VISMODEGIB
5.75	Kd	1800	nM	CHEMBL1088172
5.51	Kd	3100	nM	ROBOTNIKININ
5.51	Kd	3100	nM	CHEMBL1081726
5.35	Kd	4500	nM	CHEMBL1081555
5.24	Kd	5700	nM	CHEMBL1079557
5.06	Kd	8700	nM	CHEMBL1079558
5.05	Kd	8900	nM	CHEMBL1087150
5.05	Kd	9000	nM	CHEMBL1213326
5.00	Kd	1e+04	nM	CHEMBL1076336

PubChem BioAssay actives

22 with measured affinity, of 71 total; 18 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Vismodegib	596607: Inhibition of human SHH pathway in mouse S12 cells assessed as GLI-mediated transcriptional activity after 48 hrs by luciferase reporter gene assay	ic50	0.0150	uM
N-[(3S,5S)-1-(1,3-benzodioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl]-N-[(3-methoxyphenyl)methyl]-3,3-dimethylbutanamide	351762: Inhibition of lipid-modified (octylated) form of SHH expressed in mouse s12 cells by luciferase reporter gene assay	ic50	0.1000	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl]-N-[(3-methoxyphenyl)methyl]cyclopropanecarboxamide	351762: Inhibition of lipid-modified (octylated) form of SHH expressed in mouse s12 cells by luciferase reporter gene assay	ic50	0.1000	uM
N-[1-(1,3-benzodioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl]-N-[(3-methoxyphenyl)methyl]-2-methylpropanamide	351762: Inhibition of lipid-modified (octylated) form of SHH expressed in mouse s12 cells by luciferase reporter gene assay	ic50	0.1000	uM
(2S)-2-[[(2S,3R)-2-[[(7R,10S,13S,16S,19S,22S,25S)-25-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-acetamido-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-22-(2-carboxyethyl)-13-(carboxymethyl)-19-methyl-10,16-bis(2-methylsulfanylethyl)-9,12,15,18,21,24-hexaoxo-2-oxa-5-thia-8,11,14,17,20,23-hexazabicyclo[25.2.2]hentriaconta-1(29),27,30-triene-7-carbonyl]amino]-3-hydroxybutanoyl]amino]butanedioic acid	1947022: Binding affinity to Shh (unknown origin) assessed as dissociation constant	kd	0.1700	uM
(3S,3’R,3’aS,6’S,6aS,6bS,7’aR,9R,11aS,11bR)-3-hydroxy-3’,6’,10,11b-tetramethylspiro[1,2,3,4,6,6a,6b,7,8,11a-decahydrobenzo[a]fluorene-9,2’-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-11-one	351762: Inhibition of lipid-modified (octylated) form of SHH expressed in mouse s12 cells by luciferase reporter gene assay	ic50	0.5000	uM
(3S)-3-[[(2S,3R)-2-[[(7R,10S,13S,16S,19S,22S,25S)-25-[[(2S)-1-[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]pyrrolidine-2-carbonyl]amino]-22-(2-carboxyethyl)-13-(carboxymethyl)-19-methyl-10,16-bis(2-methylsulfanylethyl)-9,12,15,18,21,24-hexaoxo-2-oxa-5-thia-8,11,14,17,20,23-hexazabicyclo[25.2.2]hentriaconta-1(29),27,30-triene-7-carbonyl]amino]-3-hydroxybutanoyl]amino]-4-[[(2S,3R)-1-(carboxymethylamino)-3-hydroxy-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	1856129: Binding affinity to SHH (unknown origin) assessed as dissociation constant by calorimetric analysis	kd	0.5500	uM
N-[(4-chlorophenyl)methyl]-2-[(2S,6S,8E)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	0.5700	uM
(3S,3’R,3’aS,6’S,6aS,6bS,7’aR,9R,11aS,11bR)-3’,6’,10,11b-tetramethylspiro[2,3,4,6,6a,6b,7,8,11,11a-decahydro-1H-benzo[a]fluorene-9,2’-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-ol	692734: Inhibition of human Shh-induced mouse C3H10T1/2 cell differentiation after 48 hrs by alkaline phosphatase reporter assay	ic50	0.6000	uM
N-[(4-chlorophenyl)methyl]-2-[(2R,6S,8E)-5,13-dioxo-2-phenyl-1-oxa-4-azacyclotridec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	1.8000	uM
N-[(4-chlorophenyl)methyl]-2-[(2R,6S,8E)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide	1525378: Binding affinity to N-terminal sonic hedgehog (unknown origin) by surface plasmon resonance analysis	kd	3.1000	uM
N-[(4-chlorophenyl)methyl]-2-[(2S,6R,8E)-5,13-dioxo-2-phenyl-1-oxa-4-azacyclotridec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	3.1000	uM
N-[(4-chlorophenyl)methyl]-2-[(2S,6R,8E)-5,14-dioxo-2-phenyl-1-oxa-4-azacyclotetradec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	4.5000	uM
N-[(4-chlorophenyl)methyl]-2-[(6S,8E)-5,14-dioxo-1-oxa-4-azacyclotetradec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	5.7000	uM
N-[(4-chlorophenyl)methyl]-2-[(2S,6R,8E)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	8.7000	uM
N-[(4-chlorophenyl)methyl]-2-[(2R,6R,8E)-5,13-dioxo-2-phenyl-1-oxa-4-azacyclotridec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	8.9000	uM
2-[(3S,6S,8E,12S)-12-amino-3-methyl-5,13-dioxo-1-oxa-4-azacyclotridec-8-en-6-yl]-N-benzyl-N-(2-hydroxyethyl)acetamide	498489: Binding affinity to N-terminal Shh by surface plasmon resonance assay	kd	9.0000	uM
N-[(4-chlorophenyl)methyl]-2-[(6R,8E)-5,13-dioxo-1-oxa-4-azacyclotridec-8-en-6-yl]acetamide	467022: Binding affinity to recombinant Shh N-terminal peptide by surface plasma resonance	kd	10.0000	uM

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
cyclopamine	increases expression, affects cotreatment, decreases activity, decreases reaction	3
sodium arsenite	affects expression, affects methylation	2
HhAntag691	decreases reaction, increases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Cisplatin	affects cotreatment, decreases expression, decreases reaction, increases phosphorylation	2
Estradiol	affects cotreatment, decreases expression, decreases reaction, increases expression, increases reaction	2
Tretinoin	affects cotreatment, increases expression	2
4-(2-aminoethyl)benzenesulfonylfluoride	decreases reaction, affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
cobaltiprotoporphyrin	affects expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
ipriflavone	decreases reaction, increases expression	1
perfluorooctanoic acid	decreases expression	1
nickel monoxide	decreases reaction, increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
goralatide	increases expression, affects cotreatment, decreases reaction	1
chromium hexavalent ion	decreases expression	1
N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide	affects cotreatment, decreases expression, decreases reaction	1
triptonide	decreases expression	1
U 0126	affects cotreatment, decreases expression, increases reaction	1
SAG compound	increases expression	1
tofacitinib	increases expression	1
N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
GANT 61	decreases reaction, increases expression	1
Arsenic Trioxide	decreases reaction, increases phosphorylation, decreases activity	1
Bexarotene	increases expression	1
Gemcitabine	decreases expression	1
Air Pollutants	affects methylation, increases abundance	1

ChEMBL screening assays

27 unique, capped per target: 23 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1044701	Binding	Inhibition of SHH in human HEPM cells by Gli-luciferase reporter gene assay	GDC-0449-a potent inhibitor of the hedgehog pathway. — Bioorg Med Chem Lett
CHEMBL1220919	Functional	Inhibition of of N-terminal N-palmitoylated Shh-mediated Gli1 transcription in human keratinocytes after 30 hrs by real-time quantitative PCR analysis in presence of 3.6 uM Smo agonist purmorphamine	A small molecule that binds Hedgehog and blocks its signaling in human cells. — Nat Chem Biol

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6C4	SEES3-1V human SHH, clone1	Embryonic stem cell	Male
CVCL_A6C5	SEES3-1V human SHH, clone2	Embryonic stem cell	Male
CVCL_A6C6	SEES3-1V human SHH, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

304 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00003398	PHASE4	COMPLETED	Bone Marrow Transplantation in Treating Patients With Hematologic Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00046969	PHASE4	COMPLETED	Epoetin Beta in Treating Anemia in Patients With Cervical Cancer
NCT00111995	PHASE4	COMPLETED	Evaluating Aranesp® for the Treatment of Anemia in African-American Subjects With Chronic Renal Failure (CRF) Receiving Hemodialysis
NCT00117039	PHASE4	COMPLETED	A Study to Evaluate the Effectiveness of Aranesp® for Cancer Patients With Anemia
NCT00117065	PHASE4	COMPLETED	Study of Transplant Related Anemia Treated With Aranesp® (STRATA)
NCT00117117	PHASE4	COMPLETED	A Study to Assess Symptom Burden in Subjects With Nonmyeloid Malignancies Receiving Chemotherapy and Aranesp®
NCT00126334	PHASE4	COMPLETED	Conservative Versus Liberal Red Cell Transfusion in Myocardial Infarction Trial: The CRIT Pilot
NCT00153868	PHASE4	COMPLETED	A Web-based Study of Quality of Life Benefits Associated Aranesp in Anemic Patients With Cancer
NCT00168948	PHASE4	UNKNOWN	Intermittent Antimalaria Treatment With SP in African Children
NCT00173706	PHASE4	UNKNOWN	Evaluation of the Effects of L-Carnitine Injection in Patients Undergoing Hemodialysis
NCT00194857	PHASE4	TERMINATED	Treatment of Anemia and Neutropenia in HIV/HCV Coinfected Patients Treated With Pegylated Interferon and Ribavirin
NCT00204334	PHASE4	COMPLETED	Effects of Anemia Correction on Vascular and Monocyte Function in Renal Transplant Recipients
NCT00206739	PHASE4	COMPLETED	Intermittent Treatment With Sulfadoxine-pyrimethamine for Malaria Control in Infants
NCT00211120	PHASE4	TERMINATED	Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)
NCT00216541	PHASE4	COMPLETED	A Study of the Safety and Effectiveness of Epoetin Alfa on Hemoglobin Levels and Blood Transfusions in Cancer Patients Receiving Chemotherapy
NCT00223938	PHASE4	TERMINATED	Study of the Efficacy and Safety of Ferrlecit in the Maintenance Dosing in Hemodialysis Patients.
NCT00223964	PHASE4	COMPLETED	Study of the Efficacy of Two Doses of Ferrlecit in the Treatment of Iron Deficiency in Pediatric Hemodialysis Patients
NCT00224003	PHASE4	COMPLETED	Study of the Safety and Efficacy of Ferrlecit® Maintenance Dosing in Pediatric Hemodialysis Patients
NCT00224068	PHASE4	COMPLETED	Effect of Iron Therapy as an Adjunct to Epoetin Alfa in the Anemia of Cancer Chemotherapy
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00247507	PHASE4	UNKNOWN	The Effects of Acetylcysteine on Alleviating Damage of Oxidative Stress in Hemodialysis Patients
NCT00248716	PHASE4	UNKNOWN	Treatment of Anemia in the 2nd Year of Life. Comparison of the Efficacy of Two Different Iron Preparations.
NCT00283465	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Treatment With Epoetin Alfa on Hemoglobin Levels, Red Blood Cell Transfusions, and Quality of Life in Patients With Cancer Receiving Platinum-containing Chemotherapy
NCT00312871	PHASE4	TERMINATED	Effects of Early Correction of Anemia in Patients With Chronic Renal Insufficiency
NCT00315484	PHASE4	COMPLETED	Hematologic Response of Epoetin Alfa (PROCRIT) Versus Darbepoetin Alfa (ARANESP) in Chemotherapy Induced Anemia
NCT00317902	PHASE4	COMPLETED	An Open-Label Study to Evaluate the Effect of Every Other Week PROCRIT� (Epoetin Alfa) Dosing (40,000-60,000 Units) On Maintaining Quality of Life and Target Hemoglobin Levels in Anemic HIV-Infected Patients (CHAMPS II)
NCT00335023	PHASE4	COMPLETED	Well Being of Obstetric Patients on Minimal Blood Transfusions
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00377481	PHASE4	COMPLETED	COMFORT Study: A Crossover Study of NeoRecormon (Epoetin Beta) and Darbepoetin Alfa in Patients With Renal Anemia.
NCT00396435	PHASE4	COMPLETED	Correction of Anaemia and Progression of Renal Failure on Transplanted Patients
NCT00401869	PHASE4	COMPLETED	The Effect of PROCRIT (Epoetin Alfa) on Postoperative Vigor and Handgrip Strength (VIGOR Study)
NCT00413101	PHASE4	COMPLETED	A Study of NeoRecormon (Epoetin Beta) in Patients With End Stage Renal Disease.
NCT00431496	PHASE4	COMPLETED	A Study of Cinacalcet to Improve Achievement of National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Targets in Patients With End Stage Renal Disease (ESRD)
NCT00437723	PHASE4	COMPLETED	A Study of NeoRecormon in Patients With Chronic Kidney Disease.
NCT00440063	PHASE4	TERMINATED	A Study of NeoRecormon (Epoetin Beta) in Patients With Renal Anemia.
NCT00470158	PHASE4	COMPLETED	Delivery of Iron and Zinc Supplements: Evaluation of Interaction Effect on Biochemical and Clinical Outcomes
NCT00479102	PHASE4	UNKNOWN	Prevention of Iron Deficiency in 2nd Year of Life
NCT00495365	PHASE4	TERMINATED	A Dose Conversion Study of Epoetin Alfa in Subjects With the Anemia of Chronic Kidney Disease.
NCT00495378	PHASE4	TERMINATED	RAPID-2. A Study to Evaluate the Effectiveness of Alternate Dosing of PROCRIT (Epoetin Alfa) in Maintaining Hemoglobin Levels in Patients With Chemotherapy Related Anemia