IHH

Summary

IHH (Indian hedgehog signaling molecule, HGNC:5956) is a protein-coding gene on chromosome 2q35, encoding Indian hedgehog protein (Q14623). Plays a role in embryonic morphogenesis; it is involved in the regulation of endochondral skeleton formation, and the development of retinal pigment epithelium (RPE), photoreceptors and periocular tissues.

This gene encodes a member of the hedgehog family of proteins. The encoded preproprotein is proteolytically processed to generate multiple protein products, including an N-terminal fragment that is involved in signaling. Hedgehog family proteins are essential secreted signaling molecules that regulate a variety of developmental processes including growth, patterning and morphogenesis. The protein encoded by this gene specifically plays a role in bone growth and differentiation. Mutations in this gene are the cause of brachydactyly type A1, which is characterized by shortening or malformation of the fingers and toes. Mutations in this gene are also the cause of acrocapitofemoral dysplasia.

Source: NCBI Gene 3549 — RefSeq curated summary.

At a glance

• Gene–disease (curated): brachydactyly type A1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 343 total — 33 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 75
• MANE Select transcript: NM_002181

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5956
Approved symbol	IHH
Name	Indian hedgehog signaling molecule
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	HHG2, BDA1
Ensembl gene	ENSG00000163501
Ensembl biotype	protein_coding
OMIM	600726
Entrez	3549

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000295731

RefSeq mRNA: 1 — MANE Select: NM_002181 NM_002181

CCDS: CCDS33380

Canonical transcript exons

ENST00000295731 — 3 exons

Exon	Start	End
ENSE00001075355	219060153	219060921
ENSE00001075357	219057433	219057694
ENSE00001143366	219054424	219055865

Expression profiles

Bgee: expression breadth broad, 94 present calls, max score 94.15.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6021 / max 261.8117, expressed in 202 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34015	1.2454	185
34014	0.1579	67
34016	0.0866	45
34018	0.0760	34
34017	0.0362	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	94.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.24	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.28	gold quality
ileal mucosa	UBERON:0000331	82.75	silver quality
tibia	UBERON:0000979	81.89	gold quality
colonic mucosa	UBERON:0000317	81.39	gold quality
rectum	UBERON:0001052	80.48	gold quality
mucosa of sigmoid colon	UBERON:0004993	78.85	gold quality
transverse colon	UBERON:0001157	78.75	gold quality
diaphragm	UBERON:0001103	76.88	gold quality
duodenum	UBERON:0002114	76.66	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	76.25	gold quality
jejunal mucosa	UBERON:0000399	75.47	gold quality
pylorus	UBERON:0001166	74.99	gold quality
vastus lateralis	UBERON:0001379	73.95	gold quality
buccal mucosa cell	CL:0002336	73.92	gold quality
vena cava	UBERON:0004087	73.80	gold quality
hair follicle	UBERON:0002073	73.61	gold quality
jejunum	UBERON:0002115	73.15	gold quality
small intestine Peyer’s patch	UBERON:0003454	72.90	gold quality
small intestine	UBERON:0002108	72.83	gold quality
tendon of biceps brachii	UBERON:0008188	72.15	gold quality
quadriceps femoris	UBERON:0001377	71.83	gold quality
epithelial cell of pancreas	CL:0000083	71.75	gold quality
tongue squamous epithelium	UBERON:0006919	71.51	gold quality
body of stomach	UBERON:0001161	71.14	gold quality
lateral nuclear group of thalamus	UBERON:0002736	71.14	gold quality
left ventricle myocardium	UBERON:0006566	70.87	gold quality
endothelial cell	CL:0000115	70.76	gold quality
stomach	UBERON:0000945	70.53	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	249.63
E-ANND-3	yes	4.72

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, BHLHE40, BMAL1, CTNNB1, MSX2, PGR, PPARD, RUNX2, RUNX3, SMAD4, TCF7L2, ZEB1

miRNA regulators (miRDB)

63 targeting IHH, 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-5692A	100.00	74.40	6850
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6887-3P	99.66	67.83	1778

Literature-anchored findings (GeneRIF, showing 40)

• Mouse study of this member of Hedgehog family of signaling molecules in embryonic patterning and morphogenesis. Detection in target tissues requires proteoglycan/glycosaminoglycan. (PMID:11476578)
• expression is preserved in the growth plate of human fetuses affected with fibroblast growth factor receptor type 3 activating mutations (PMID:12368206)
• novel mutation causes brachydactyly type A1 (PMID:12384778)
• A novel missense mutation in the IHH gene mapping to chromosome 5 has been identified identified in all patients of a brachydactyly type A1 family. (PMID:12525541)
• Homozygous mutations in this gene cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. (PMID:12632327)
• 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)
• 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)
• IHH is involved in the development of enteric nervous system but is not a major gene in Hirschsprung’s disease. (PMID:14651602)
• We report that Indian hedgehog (Ihh) is expressed by mature colonocytes and regulates their differentiation in vitro and in vivo. (PMID:14770182)
• Ihh gene transfer into hTERT stromal cells enhanced their hematopoietic supporting potential in coculture with CD34+ cells (PMID:15105288)
• aberrant activation of the Ihh signaling pathway contributes to tumor development in pancreatic cancer (PMID:15146555)
• 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)
• DNA sequence analysis revealed a heterozygous C to T transition at nucleotide 461 of IHH, resulting in a novel T154I substitution. The T154I mutation co-segregated with all affected individuals in the family. (PMID:16871364)
• the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment (PMID:17360475)
• Ihh was expressed in 100% of conventional and clear cell chondrosarcomas, especially in matrix-rich areas. Mesenchymal chondrosarcomas revealed only focal expression of Ihh in matrix-rich areas.Ihh was absent or focally expressed in enchondromas. (PMID:17387386)
• D100N mutation must have arisen independently in these families, suggesting that 298G may be a mutational hot spot. (PMID:17486609)
• enhanced signaling by Ihh can modulate the proliferation and differentiation of splenic B lymphocytes and thymic T lymphocytes during bone marrow hematopoiesis in vivo (PMID:17962696)
• A single smino acid deletion in IHH causes mild brachdactyly A1. (PMID:18629882)
• its signal transduction regulates tumor development. (review) (PMID:18788453)
• A novel role of Runx2 in up-regulating the vicious cycle of metastatic bone disease, in addition to Runx2 regulation of genes related to progression of tumor metastasis. (PMID:18829534)
• Hh signaling is important in the pathogenesis of B-CLL and, hence, may be a potential therapeutic target (PMID:19074837)
• Ihh (Indian hedgehog homolog) signals via the BMP(bone morphogenetic protein) pathway, and specifically through BMP4, to promote endothelial cell differentiation from pluripotent cells (PMID:19213939)
• Data show that all of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH. (PMID:19277064)
• An association of paracrine Hedgehog signaling with several gastrointestinal patterning events involving serosa, pylorus, and villus smooth muscle is shown. (PMID:19445942)
• BDA1 caused by a heterozygous mutation in the IHH gene on chromosome 5 was investigated in a large Swedish family. (PMID:19464397)
• Methylation analysis revealed that IHH promoter was hypermethylated in colon cancer cell lines. (PMID:19856079)
• Indian hedgehog protein was detected in cystic tubules within human dysplastic kidneys; these molecules modify severity of this congenital malformation. Hedgehog signaling may be important stimulus for renal cyst formation. (PMID:20007344)
• This data confirms genetic heterogeneity in Brachydactyly A1 (BDA1) and demonstrates that mutations upstream of IHH can result in BDA1. (PMID:20683927)
• VLDL carries Ihh throughout the body in mammals (PMID:20839884)
• down-regulation of indian hedgehog expression as a result of hypermethylation, may be an early event in colorectal carcinogenesis (PMID:20854074)
• The temporal increase in endometrial IHH during the secretory phase, and their modulation by CDB-2914 suggests progestin role in endometrial differentiation and implantation. (PMID:20881264)
• the observed duplications lead to a misexpression and/or overexpression of IHH and by this affect the complex regulatory signaling network during digit and skull development. (PMID:21167467)
• Nuclear and cytoplasmic endometrial expression of Indian hedgehog is decreased in women with endometriosis. (PMID:21640343)
• Studies indicate that IHH is required for normal chondrocyte proliferation during both embryonic and postnatal growth. (PMID:21642379)
• Studies indicate that pathways of Hedgehog (Hh), Wnt and Notch, which regulate development during embryonic life and somatic stem cells (SCs) in the adult organism, can be reactivated in malignancies and support tumor-initiating cells (TIC) scompartment. (PMID:22123293)
• A large duplication involving the IHH locus mimics acrocallosal syndrome (PMID:22234151)
• A missense mutation in IHH gene is observed in an individual affected by brachydactyly type A1. (PMID:22406540)
• Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage. (PMID:22469853)
• Results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells through a hedgehog/Gli1-independent pathway. (PMID:22486854)
• Ihh-induced Nkx3.2 degradation requires Wnt5a, which is capable of triggering Nkx3.2 degradation (PMID:22507129)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhh	ENSDARG00000037062
mus_musculus	Ihh	ENSMUSG00000006538
rattus_norvegicus	Ihh	ENSRNOG00000018059
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		WBGENE00006953
caenorhabditis_elegans		WBGENE00006954

Paralogs (2): DHH (ENSG00000139549), SHH (ENSG00000164690)

Protein

Protein identifiers

Indian hedgehog protein — Q14623 (reviewed: Q14623)

Alternative names: HHG-2

All UniProt accessions (1): Q14623

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in embryonic morphogenesis; it is involved in the regulation of endochondral skeleton formation, and the development of retinal pigment epithelium (RPE), photoreceptors and periocular tissues. The C-terminal part of the indian 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 followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated N-product. Both activities occur in the endoplasmic reticulum. Plays a role in hedgehog paracrine signaling. Associated with the very-low-density lipoprotein (VLDL) particles to function as a circulating morphogen for endothelial cell integrity maintenance. The dually lipidated indian hedgehog protein N-product is a morphogen which is essential for a variety of patterning events during development. Binds to the patched (PTCH1) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. Plays a role in morphogenesis of the skeleton by coordinating growth and differentiation of the endochondral skeleton. Positively regulates PTHLH expression during endochondral bone formation preventing chondrocyte hypertrophy. In contrast, participates in normal chondrocyte proliferation in a PTHLH-independent pathway.

Subunit / interactions. Multimer. Interacts with BOC and CDON. Interacts with PTCH1. Interacts with glypican GPC3.

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

Tissue specificity. Expressed in embryonic lung, and in adult kidney and liver.

Post-translational modifications. Cholesterylation is required for N-product targeting to lipid rafts and multimerization. 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-product. The N-product is the active species in both local and long-range signaling, whereas the C-product is degraded in the endoplasmic reticulum. N-palmitoylation by HHAT of N-product is required for indian hedgehog protein N-product multimerization and full activity.

Disease relevance. Brachydactyly A1 (BDA1) [MIM:112500] An autosomal dominant form of brachydactyly, a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type A1 is characterized by middle phalanges of all the digits rudimentary or fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are short. Some BDA1 affected individuals exhibit short stature. The disease is caused by variants affecting the gene represented in this entry. Acrocapitofemoral dysplasia (ACFD) [MIM:607778] An autosomal recessive disorder characterized by short stature of variable severity with postnatal onset. The most constant radiographic abnormalities are observed in the tubular bones of the hands and in the proximal part of the femur. Cone-shaped epiphyses or a similar epiphyseal configuration with premature epimetaphyseal fusion result in shortening of the skeletal components involved. Cone-shaped epiphyses are also present to a variable extent at the shoulders, knees and ankles. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds calcium and zinc ions; this stabilizes the protein fold and is essential for protein-protein interactions mediated by this domain.

Similarity. Belongs to the hedgehog family.

RefSeq proteins (1): NP_002172* (*=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 (48 total): binding site 12, strand 9, sequence variant 6, helix 6, site 4, sequence conflict 3, chain 2, lipid moiety-binding region 2, signal peptide 1, glycosylation site 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3K7I	X-RAY DIFFRACTION	1.44
3K7G	X-RAY DIFFRACTION	1.5
3K7H	X-RAY DIFFRACTION	1.5
3N1F	X-RAY DIFFRACTION	1.6
3N1M	X-RAY DIFFRACTION	1.69
3K7J	X-RAY DIFFRACTION	1.9
3N1O	X-RAY DIFFRACTION	2.55
3N1P	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14623-F1	84.84	0.54

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): 202–203 (cleavage; by autolysis); 248 (involved in cholesterol transfer); 272 (involved in auto-cleavage); 275 (essential for auto-cleavage)

Ligand- & substrate-binding residues (12): 134; 136; 145; 152; 187; 94; 95; 95; 100; 130; 131; 131

Post-translational modifications (2): 28, 202

Glycosylation sites (1): 282

Mutagenesis-validated functional residues (1):

Position	Phenotype
95	increases the lysosomal degradation of the indian hedgehog protein n-product.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-5358346	Hedgehog ligand biogenesis
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-8941284	RUNX2 regulates chondrocyte maturation
R-HSA-9758920	Formation of lateral plate mesoderm

MSigDB gene sets: 517 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_RESPONSE_TO_ESTRADIOL

GO Biological Process (63): skeletal system development (GO:0001501), branching involved in blood vessel morphogenesis (GO:0001569), osteoblast differentiation (GO:0001649), in utero embryonic development (GO:0001701), cell fate specification (GO:0001708), heart looping (GO:0001947), positive regulation of mesenchymal cell proliferation (GO:0002053), epithelial cell morphogenesis (GO:0003382), retinal pigment epithelium development (GO:0003406), chondrocyte differentiation involved in endochondral bone morphogenesis (GO:0003413), proteoglycan metabolic process (GO:0006029), smoothened signaling pathway (GO:0007224), cell-cell signaling (GO:0007267), response to mechanical stimulus (GO:0009612), embryonic pattern specification (GO:0009880), regulation of gene expression (GO:0010468), intein-mediated protein splicing (GO:0016539), protein autoprocessing (GO:0016540), vitelline membrane formation (GO:0030704), pancreas development (GO:0031016), negative regulation of chondrocyte differentiation (GO:0032331), response to estradiol (GO:0032355), positive regulation of collagen biosynthetic process (GO:0032967), negative regulation of T cell differentiation in thymus (GO:0033085), negative regulation of immature T cell proliferation in thymus (GO:0033088), positive regulation of T cell differentiation in thymus (GO:0033089), multicellular organism growth (GO:0035264), chondrocyte proliferation (GO:0035988), regulation of growth (GO:0040008), embryonic digit morphogenesis (GO:0042733), negative regulation of apoptotic process (GO:0043066), bone resorption (GO:0045453), positive regulation of smoothened signaling pathway (GO:0045880), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of alpha-beta T cell differentiation (GO:0046638), negative regulation of alpha-beta T cell differentiation (GO:0046639), negative regulation of eye pigmentation (GO:0048074), cell maturation (GO:0048469), embryonic digestive tract morphogenesis (GO:0048557), embryonic camera-type eye morphogenesis (GO:0048596)

GO Molecular Function (8): patched binding (GO:0005113), calcium ion binding (GO:0005509), peptidase activity (GO:0008233), 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 (9): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), extracellular region (GO:0005576), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Signaling by Hedgehog	2
Hedgehog ‘on’ state	2
GPCR ligand binding	1
Hedgehog ligand biogenesis	1
Hh mutants abrogate ligand secretion	1
RUNX2 regulates bone development	1
Gastrulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity, acting on a protein	2
catalytic activity	2
cellular anatomical structure	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
system development	1
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
ossification	1
cell differentiation	1
chordate embryonic development	1
cell fate commitment	1
cellular developmental process	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
cell morphogenesis	1
epithelial cell development	1
retina development in camera-type eye	1
epithelium development	1
chondrocyte differentiation	1
endochondral bone morphogenesis	1
cartilage development involved in endochondral bone morphogenesis	1
glycoprotein metabolic process	1
cell surface receptor signaling pathway	1
cell communication	1
signaling	1
response to external stimulus	1
response to abiotic stimulus	1
pattern specification process	1
embryo development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
protein splicing	1
protein processing	1
developmental process involved in reproduction	1

Protein interactions and networks

STRING

2363 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IHH	PTCH1	Q13635	999
IHH	SMO	Q99835	996
IHH	PTCH2	Q9Y6C5	995
IHH	HHIP	Q96QV1	984
IHH	GLI1	P08151	961
IHH	PTHLH	P12272	956
IHH	FGFR2	P18443	861
IHH	RUNX2	Q13950	842
IHH	GLI2	P10070	834
IHH	GLI3	P10071	818
IHH	FGF2	P09038	808
IHH	BMPR1B	P78366	800
IHH	SUFU	Q9UMX1	792
IHH	FGF13	Q92913	787
IHH	ACAN	P16112	761

IntAct

6 interactions, top by confidence:

A	B	Type	Score
IHH	BOC	psi-mi:“MI:0407”(direct interaction)	0.560
IHH	CDON	psi-mi:“MI:0407”(direct interaction)	0.440
HHIP	IHH	psi-mi:“MI:0915”(physical association)	0.400
RHOD	IHH	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (1): RHOD (Two-hybrid)

ESM2 similar proteins: A0A1D5PJB7, A1A4Q9, A5YM72, A6NLP5, D3KCC4, I3L5V6, O43292, P10938, Q00973, Q05B52, Q09200, Q10468, Q14623, Q148G5, Q16586, Q2V8X7, Q3SZV0, Q561R2, Q5E9M9, Q5M868, Q5ZL13, Q66H45, Q69ZF3, Q6P3D0, Q6P7A1, Q6P9Z4, Q6SZW1, Q6TEC1, Q6ZPS2, Q7TMC8, Q864R5, Q86TX2, Q8IXI1, Q8N0W3, Q8N3Y3, Q8N6R0, Q8NF37, Q8NI29, Q8TCD5, Q8VBW8

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

5 interactions.

A	Effect	B	Mechanism
IHH	up-regulates	BMP2
IHH	“down-regulates activity”	PTCH1	binding
IHH	“down-regulates activity”	PTCH2	binding
HHIP	“down-regulates activity”	IHH	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	16
Uncertain significance	191
Likely benign	58
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1217222	NM_002181.4(IHH):c.478C>T (p.Arg160Cys)	Pathogenic
1385830	NM_002181.4(IHH):c.2T>A (p.Met1Lys)	Pathogenic
1395100	NM_002181.4(IHH):c.77G>A (p.Trp26Ter)	Pathogenic
1481193	NM_002181.4(IHH):c.172G>T (p.Glu58Ter)	Pathogenic
1484276	NM_002181.4(IHH):c.527_530del (p.Asp176fs)	Pathogenic
1803981	NM_002181.4(IHH):c.415dup (p.His139fs)	Pathogenic
2151961	NM_002181.4(IHH):c.172G>A (p.Glu58Lys)	Pathogenic
2697447	NM_002181.4(IHH):c.714dup (p.Thr239fs)	Pathogenic
2699120	NM_002181.4(IHH):c.434del (p.His145fs)	Pathogenic
2738245	NM_002181.4(IHH):c.540C>G (p.Tyr180Ter)	Pathogenic
2772702	NM_002181.4(IHH):c.931_937dup (p.Gln313fs)	Pathogenic
2821742	NM_002181.4(IHH):c.399G>A (p.Trp133Ter)	Pathogenic
2846342	NM_002181.4(IHH):c.2T>G (p.Met1Arg)	Pathogenic
2853436	NM_002181.4(IHH):c.2T>C (p.Met1Thr)	Pathogenic
3247493	NC_000002.11:g.(?219919929)(219942948_?)del	Pathogenic
3341144	NM_002181.4(IHH):c.532G>C (p.Val178Leu)	Pathogenic
3341145	NM_002181.4(IHH):c.319del (p.Cys107fs)	Pathogenic
3341146	NM_002181.4(IHH):c.797dup (p.Arg267fs)	Pathogenic
3341147	NM_002181.4(IHH):c.541del (p.Glu181fs)	Pathogenic
3341148	IHH, COMPLETE GENE DELETION	Pathogenic
3653496	NM_002181.4(IHH):c.286_295dup (p.Ala99fs)	Pathogenic
3663894	NM_002181.4(IHH):c.101dup (p.Ser36fs)	Pathogenic
3712114	NM_002181.4(IHH):c.274A>C (p.Lys92Gln)	Pathogenic
3727608	NM_002181.4(IHH):c.217del (p.Arg73fs)	Pathogenic
4820635	NM_002181.4(IHH):c.374_375del (p.Val125fs)	Pathogenic
8866	NM_002181.4(IHH):c.283G>A (p.Glu95Lys)	Pathogenic
8868	NM_002181.4(IHH):c.300C>A (p.Asp100Glu)	Pathogenic
8869	NM_002181.4(IHH):c.298G>A (p.Asp100Asn)	Pathogenic
8870	NM_002181.4(IHH):c.137C>T (p.Pro46Leu)	Pathogenic
8871	NM_002181.4(IHH):c.569T>C (p.Val190Ala)	Pathogenic

SpliceAI

576 predictions. Top by Δscore:

Variant	Effect	Δscore
2:219055861:GTGCT:G	acceptor_gain	1.0000
2:219055862:TGCT:T	acceptor_gain	1.0000
2:219055863:GCTC:G	acceptor_loss	1.0000
2:219055864:CT:C	acceptor_gain	1.0000
2:219055865:TC:T	acceptor_loss	1.0000
2:219055866:C:CC	acceptor_gain	1.0000
2:219055866:C:CG	acceptor_loss	1.0000
2:219055867:T:A	acceptor_loss	1.0000
2:219057432:CCGGA:C	donor_gain	1.0000
2:219057523:A:AC	donor_gain	1.0000
2:219057524:C:CC	donor_gain	1.0000
2:219057527:A:AC	donor_gain	1.0000
2:219055868:G:C	acceptor_gain	0.9900
2:219057426:GGCTC:G	donor_loss	0.9900
2:219057427:GCTCA:G	donor_loss	0.9900
2:219057428:CTCAC:C	donor_loss	0.9900
2:219057429:TCACC:T	donor_loss	0.9900
2:219057430:CA:C	donor_loss	0.9900
2:219057431:A:AG	donor_loss	0.9900
2:219057432:C:CA	donor_loss	0.9900
2:219057527:ATTG:A	donor_gain	0.9900
2:219057528:T:C	donor_gain	0.9900
2:219057695:C:CC	acceptor_gain	0.9900
2:219060148:CTCA:C	donor_loss	0.9900
2:219060149:TCACC:T	donor_loss	0.9900
2:219060150:CACCT:C	donor_loss	0.9900
2:219060151:A:T	donor_loss	0.9900
2:219060152:C:CT	donor_loss	0.9900
2:219055863:GCT:G	acceptor_gain	0.9800
2:219055864:CTCTG:C	acceptor_gain	0.9800

AlphaMissense

2632 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:219057441:A:T	V190D	1.000
2:219057444:G:A	S189F	1.000
2:219057445:A:G	S189P	1.000
2:219057446:G:C	C188W	1.000
2:219057447:C:T	C188Y	1.000
2:219057448:A:G	C188R	1.000
2:219057449:A:C	H187Q	1.000
2:219057449:A:T	H187Q	1.000
2:219057451:G:C	H187D	1.000
2:219057451:G:T	H187N	1.000
2:219057453:A:T	V186E	1.000
2:219057455:G:C	H185Q	1.000
2:219057455:G:T	H185Q	1.000
2:219057457:G:C	H185D	1.000
2:219057466:A:G	S182P	1.000
2:219057479:C:A	W177C	1.000
2:219057479:C:G	W177C	1.000
2:219057481:A:G	W177R	1.000
2:219057481:A:T	W177R	1.000
2:219057483:T:A	D176V	1.000
2:219057485:A:C	F175L	1.000
2:219057485:A:T	F175L	1.000
2:219057486:A:G	F175S	1.000
2:219057487:A:G	F175L	1.000
2:219057493:C:G	A173P	1.000
2:219057501:G:T	A170E	1.000
2:219057513:A:G	L166P	1.000
2:219057513:A:T	L166Q	1.000
2:219057544:A:G	S156P	1.000
2:219057546:G:T	T155K	1.000

dbSNP variants (sampled 300 via entrez): RS1000452249 (2:219054768 C>A), RS1000664448 (2:219062862 G>A), RS1000671214 (2:219055569 C>A,T), RS1001054522 (2:219062399 G>C), RS1001167973 (2:219058483 C>T), RS1001220317 (2:219058268 G>C), RS1002170456 (2:219059742 G>A,C), RS1002222600 (2:219059501 G>A), RS1002351841 (2:219056799 A>G), RS1002466312 (2:219057046 G>T), RS1002684064 (2:219058159 G>A,T), RS1002800481 (2:219058477 C>T), RS1003215585 (2:219054994 G>A), RS1003227424 (2:219060878 G>A), RS1003235437 (2:219054150 C>T)

Disease associations

OMIM: gene MIM:600726 | disease phenotypes: MIM:607778, MIM:112500, MIM:142623, MIM:602875

GenCC curated gene-disease

Disease	Classification	Inheritance
brachydactyly type A1	Definitive	Autosomal dominant
acrocapitofemoral dysplasia	Definitive	Autosomal recessive

Mondo (6): acrocapitofemoral dysplasia (MONDO:0011907), brachydactyly type A1 (MONDO:0007215), brachydactyly type A1A (MONDO:0020701), Hirschsprung disease, susceptibility to, 1 (MONDO:0007723), brachydactyly (MONDO:0021004), acromesomelic dysplasia 1, Maroteaux type (MONDO:0011275)

Orphanet (4): Acrocapitofemoral dysplasia (Orphanet:63446), Brachydactyly type A1 (Orphanet:93388), Hirschsprung disease (Orphanet:388), Acromesomelic dysplasia, Maroteaux type (Orphanet:40)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000887	Cupped ribs
HP:0001032	Absent distal interphalangeal creases
HP:0001156	Brachydactyly
HP:0001169	Broad palm
HP:0001204	Distal finger symphalangism
HP:0001216	Delayed ossification of carpal bones
HP:0001230	Broad metacarpals
HP:0001249	Intellectual disability
HP:0001762	Talipes equinovarus
HP:0001773	Short foot
HP:0001792	Small nail
HP:0001799	Short nail
HP:0001821	Broad nail
HP:0002650	Scoliosis
HP:0002652	Skeletal dysplasia
HP:0002750	Delayed skeletal maturation
HP:0002812	Coxa vara
HP:0002866	Hypoplastic iliac wing
HP:0002869	Flared iliac wing
HP:0002938	Lumbar hyperlordosis
HP:0002970	Genu varum
HP:0002983	Micromelia
HP:0002984	Hypoplasia of the radius

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000174_15	Height	2.000000e-08
GCST000175_19	Height	1.000000e-06
GCST000611_11	Height	5.000000e-06
GCST000817_22	Height	2.000000e-07
GCST003336_12	Waist circumference adjusted for body mass index	4.000000e-07
GCST008839_215	Height	2.000000e-10
GCST008839_523	Height	2.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D059327	Brachydactyly	C05.660.585.262; C16.131.621.585.262
C564334	Acrocapitofemoral Dysplasia (supp.)
C535661	Acromesomelic dysplasia, Maroteaux type (supp.)
C537088	Brachydactyly type A1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
potassium perchlorate	decreases expression	1
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases reaction, increases expression, affects cotreatment	1
Chir 99021	decreases reaction, increases expression, affects cotreatment	1
Resveratrol	decreases expression	1
Fulvestrant	decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Dexamethasone	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Fluorouracil	decreases expression	1
Progesterone	decreases expression, affects cotreatment	1
Theophylline	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression, affects cotreatment, decreases reaction	1
Urethane	increases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8I4	Abcam HCT 116 IHH KO	Cancer cell line	Male
CVCL_B9KD	Abcam A-549 IHH KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility
NCT04730128	Not specified	COMPLETED	Translation and Validation of a Disease-specific Questionnaire for Hirschsprung’s Disease in Danish Patients
NCT04837963	Not specified	COMPLETED	Does Hirschsprung Disease Increase the Risk of Febrile Urinary Tract Infection in Children
NCT04957667	Not specified	COMPLETED	Scintigraphic Defecography for Evaluation of Functional Outcome in an Adult Hirschsprung Population
NCT05038345	Not specified	TERMINATED	Hirschsprung Disease Trends in the United States: Analysis of the National Inpatient Sample
NCT05044741	Not specified	COMPLETED	Risk Factors of Perforated HSCR in Neonates
NCT05293353	Not specified	UNKNOWN	Neokare Safety and Tolerability Assessment in Neonates With GI Problems
NCT05307419	Not specified	UNKNOWN	Full Thickness vs. Rectal Suction Biopsy in the Diagnosis of Hirschsprungs Disease
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT05655845	Not specified	UNKNOWN	Risk Factors for Bowel Dysfunction at Preschool and Early Childhood Age in Children With Hirschsprung Disease
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06197061	Not specified	UNKNOWN	Comparison of Robot-assisted With Laparoscopic-assisted Modified Soave Procedure for Classical Hirschsprung Disease
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)
NCT06650683	Not specified	RECRUITING	Impact of Providing Nursing Support on Parental Stress Related to Preoperative Care of a Newborn with Hirschsprung’s Disease