TGM3

Summary

TGM3 (transglutaminase 3, HGNC:11779) is a protein-coding gene on chromosome 20p13, encoding Protein-glutamine gamma-glutamyltransferase E (Q08188). Catalyzes the calcium-dependent formation of isopeptide cross-links between glutamine and lysine residues in various proteins, as well as the conjugation of polyamines to proteins.

Transglutaminases are enzymes that catalyze the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. While the primary structure of transglutaminases is not conserved, they all have the same amino acid sequence at their active sites and their activity is calcium-dependent. The protein encoded by this gene consists of two polypeptide chains activated from a single precursor protein by proteolysis. The encoded protein is involved the later stages of cell envelope formation in the epidermis and hair follicle.

Source: NCBI Gene 7053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): uncombable hair syndrome 2 (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 174 total — 1 pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11779
Approved symbol	TGM3
Name	transglutaminase 3
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	TGE
Ensembl gene	ENSG00000125780
Ensembl biotype	protein_coding
OMIM	600238
Entrez	7053

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000381458, ENST00000463090

RefSeq mRNA: 1 — MANE Select: NM_003245 NM_003245

CCDS: CCDS33435

Canonical transcript exons

ENST00000381458 — 13 exons

Exon	Start	End
ENSE00000655744	2310178	2310417
ENSE00000655746	2311011	2311129
ENSE00000655748	2312898	2313026
ENSE00000858628	2309657	2309830
ENSE00001609199	2340434	2341079
ENSE00001622482	2339854	2339987
ENSE00001632148	2328120	2328365
ENSE00001671589	2332002	2332310
ENSE00001696552	2325849	2325952
ENSE00001761978	2335116	2335273
ENSE00001884839	2296001	2296070
ENSE00003526860	2317068	2317245
ENSE00003671503	2317350	2317485

Expression profiles

Bgee: expression breadth ubiquitous, 120 present calls, max score 99.89.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.2833 / max 1285.9542, expressed in 94 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183151	3.2833	94

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.89	gold quality
esophagus mucosa	UBERON:0002469	99.00	gold quality
skin of leg	UBERON:0001511	94.25	gold quality
zone of skin	UBERON:0000014	93.77	gold quality
skin of abdomen	UBERON:0001416	93.22	gold quality
esophagus	UBERON:0001043	80.35	gold quality
right uterine tube	UBERON:0001302	75.64	gold quality
tonsil	UBERON:0002372	71.64	gold quality
minor salivary gland	UBERON:0001830	67.66	gold quality
vagina	UBERON:0000996	67.57	gold quality
ectocervix	UBERON:0012249	67.31	gold quality
gall bladder	UBERON:0002110	66.94	gold quality
blood	UBERON:0000178	65.93	gold quality
saliva-secreting gland	UBERON:0001044	64.49	gold quality
uterine cervix	UBERON:0000002	64.18	gold quality
granulocyte	CL:0000094	62.73	gold quality
right coronary artery	UBERON:0001625	61.73	gold quality
fallopian tube	UBERON:0003889	61.38	gold quality
lower esophagus	UBERON:0013473	59.59	gold quality
lower esophagus muscularis layer	UBERON:0035833	59.47	gold quality
fundus of stomach	UBERON:0001160	59.07	gold quality
right lobe of liver	UBERON:0001114	58.45	gold quality
temporal lobe	UBERON:0001871	58.25	gold quality
amygdala	UBERON:0001876	58.21	gold quality
bone marrow	UBERON:0002371	57.98	gold quality
rectum	UBERON:0001052	57.22	gold quality
endocervix	UBERON:0000458	57.17	gold quality
body of stomach	UBERON:0001161	57.11	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	56.29	gold quality
body of pancreas	UBERON:0001150	56.06	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

32 targeting TGM3, 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-4283	100.00	66.42	2097
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-302C-5P	99.97	72.56	3642
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-1468-3P	99.96	72.74	3797
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-6864-5P	98.38	66.59	1079
HSA-MIR-224-5P	98.33	70.12	1256
HSA-MIR-637	97.91	64.05	1517

Literature-anchored findings (GeneRIF, showing 40)

• epidermal transglutaminase (type 3) is the dominant autoantigen in dermatitis herpetiformis (PMID:11901200)
• x-ray crystallography in the presence of Ca2+ and/or Mg+2 shows Ca2+ binding in both sites two and three cooperate in opening the channel (PMID:12679341)
• Expression in upper layers of epidermis. Diffuse cytoplasmic distribution in vitro consistent with its proposed role in early phase of cornified cell envelope assembly in cytoplasm. (PMID:12850301)
• transglutaminase 3 is regulated by guanine nucleotides and calcium/magnesium (PMID:14645372)
• Crystal structure of transglutaminase 3 in complex with GMP (PMID:15084592)
• LEKTI deficiency in the epidermis and in hair roots at the protein level and an aberrant expression of other proteins, especially transglutaminase1 and 3, which may account for the impaired epidermal barrier in Netherton syndrome (PMID:15304086)
• upstream sequence of Ets core motif is critical for the expression of TGM3 in cells cultured in vitro. (PMID:15335352)
• In HEK 293T cell culture, transglutaminase 3 cross-links the N-terminal fragments of mutant huntingtin protein, therefore it could be involved in the cross-linking of huntingtin into intranuclear inclusions in Huntington disease. (PMID:15715085)
• We conclude from these in vitro experiments that the E1–E4 protein is cross-linked by transglutaminase 3, and that E1–E4 expression in differentiated keratinocytes induces morphologic abnormalities of the cornified cell envelope. (PMID:16257432)
• BCSG-1 significantly correlates with levels of transglutaminase-3 and may have a role in progression of breast cancer (PMID:16786148)
• Reduced expression of transglutaminase 3 (TGM3) may play an important role in esophageal carcinogenesis. (PMID:16804985)
• Using a new antibody raised in goat with specificity confirmed using a separately cloned recombinant protein, we have confirmed findings of Sardy et al. suggesting TG3 is the autoantigen of dermatitis herpetiformis (PMID:17205060)
• detected two splicing variants for TG3, as the transcription of these mRNAs appears to be not regulated during differentiation and in pathologies involving tranglutaminase activity (PMID:17380116)
• TGase 3-driven specific isopeptide bonds between intermediate filaments and keratin associated proteins participate to the progressive scaffolding of the hair shaft (PMID:18719606)
• Cathepsin L and transglutaminase 3 could be involved in the pathway that leads to terminal differentiation, not only in the epidermis but also in the human hair follicle and nail unit. (PMID:19005484)
• Reduced TGM3 expression is associated with esophageal squamous cell carcinoma. (PMID:19142970)
• Lack of TGM3 expression is associated with oral squamous cell carcinoma. (PMID:19522851)
• findings lend credence to the notion that TG3 and TG6 are involved in the gluten-induced autoimmune responses of dermatitis herpetiformis and gluten ataxia (PMID:20300788)
• new information on the specific distribution of TGase 3 (PMID:20716179)
• TGM3 in immunoglobulin A (IgA) and TGM3 immune complexes is responsible for cross-linking and tight binding of IgA to connective tissue in the dermis and explains the IgA deposits in dermatitis herpetiformis skin long after signs of disease are resolved. (PMID:21335491)
• The low expression of TGM3 may contribute to the carcinogenesis and development of laryngeal carcinoma. (PMID:22506423)
• Genetic variation in the epidermal transglutaminase genes is not associated with atopic dermatitis. (PMID:23189155)
• mRNA expression of transglutaminase 1 and transglutaminase 3 was significantly decreased in patients with chronic periodontitis compared with a healthy control group. (PMID:24112124)
• TGM3, a candidate tumor suppressor, contributes to the carcinogenesis and development of human head and neck cancer. (PMID:24289313)
• New basal cell carcinoma susceptibility loci were identified at TGM3 (rs214782) and RGS22(rs7006527). (PMID:24403052)
• IgA-anti-TG1 antibodies were found in 2% and IgA-anti-TG3 antibodies in 3% of patients with active atopic dermatitis (AD). Two out of the 5 patients with AD and concomitant celiac disease had IgA-anti-TG1 and IgA-anti-TG2 antibodies. (PMID:24885370)
• Transglutaminase 3 present in the IgA aggregates in dermatitis herpetiformis skin is enzymatically active and binds soluble fibrinogen. (PMID:25178107)
• Levels of TG3-IgA IC significantly elevated in plasma as well as in serum samples of untreated patients with dermatitis herpetiformis compared with healthy controls. (PMID:27106676)
• Our data collectively demonstrate that TGM3 can be a candidate tumor suppressor that is able to induce esophageal cancer cell proliferation and migration (PMID:27430245)
• Data indicate a decrease in transglutaminases TG1 and TG3 transcripts by about 70% in foreskins from patients with balanitis xerotica obliterans (BXO) BXO in comparison with patients without BXO and an increase in transglutaminase TG2 mRNA levels by 2.9 fold. (PMID:27649154)
• The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. (PMID:27866708)
• studies demonstrate that TGase-catalyzed transamidation and activation of rac1 and cdc42 results from stimulation of multiple types of receptors and this novel signaling pathway can regulate dendritic spine morphology and plasticity. (PMID:28161375)
• Cultured duodenal biopsies from patients with dermatitis herpetiformis produce transglutaminase-3 antibodies. (PMID:29182792)
• Patents having higher level of TGM-3 expression have good response to chemo-radiotherapy and also have better overall survival. TGM-3 may serve as a candidate biomarker for responsiveness to chemo-radiotherapy treatment in oral squamous cell carcinoma patients (PMID:29953521)
• TGM3 played an important role in OL malignant transformation (PMID:30172723)
• aberrant TGase 1 and TGase 3 localization and distribution are closely related to hyper-keratinization in Oral lichen planus. (PMID:30213231)
• Transglutaminase 3 Promotes Skin Inflammation in Atopic Dermatitis by Activating Monocyte-Derived Dendritic Cells via DC-SIGN. (PMID:31425706)
• TGM3 promotes epithelial-mesenchymal transition and hepatocellular carcinogenesis and predicts poor prognosis for patients after curative resection. (PMID:31822388)
• TGM3 functions as a tumor suppressor by repressing epithelialtomesenchymal transition and the PI3K/AKT signaling pathway in colorectal cancer. (PMID:32020212)
• Downregulation of miR106b3p increases sensitivity to cisplatin in esophageal cancer cells by targeting TGM3. (PMID:33899115)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgm8	ENSDARG00000097651
danio_rerio	tgm5l	ENSDARG00000098837
mus_musculus	Tgm3	ENSMUSG00000027401
rattus_norvegicus	Tgm3	ENSRNOG00000006753

Paralogs (8): TGM1 (ENSG00000092295), TGM5 (ENSG00000104055), F13A1 (ENSG00000124491), TGM7 (ENSG00000159495), TGM4 (ENSG00000163810), EPB42 (ENSG00000166947), TGM6 (ENSG00000166948), TGM2 (ENSG00000198959)

Protein

Protein identifiers

Protein-glutamine gamma-glutamyltransferase E — Q08188 (reviewed: Q08188)

Alternative names: Transglutaminase E, Transglutaminase-3

All UniProt accessions (1): Q08188

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the calcium-dependent formation of isopeptide cross-links between glutamine and lysine residues in various proteins, as well as the conjugation of polyamines to proteins. Involved in the formation of the cornified envelope (CE), a specialized component consisting of covalent cross-links of proteins beneath the plasma membrane of terminally differentiated keratinocytes. Catalyzes small proline-rich proteins (SPRR1 and SPRR2) and LOR cross-linking to form small interchain oligomers, which are further cross-linked by TGM1 onto the growing CE scaffold. In hair follicles, involved in cross-linking structural proteins to hardening the inner root sheath.

Subunit / interactions. Consists of two polypeptide chains, which are synthesized as a precursor form of a single polypeptide.

Subcellular location. Cytoplasm.

Post-translational modifications. Activated by proteolytic processing. In vitro activation is commonly achieved by cleavage with dispase, a neutral bacterial protease. Dispase cleavage site was proposed to lie between Ser-470 and Ser-471 or between Pro-465 and Phe-466. Physiological activation may be catalyzed by CTSL and, to a lesser extent, by CTSS, but not by CTSB, CTSD nor CTSV.

Disease relevance. Uncombable hair syndrome 2 (UHS2) [MIM:617251] A form of uncombable hair syndrome, a condition characterized by scalp hair that is impossible to comb due to the haphazard arrangement of the hair bundles. A characteristic morphologic feature is a triangular to reniform to heart shape on cross-sections, and a groove, canal or flattening along the entire length of the hair. Most individuals are affected early in childhood and the hair takes on a spun-glass appearance with the hair becoming dry, curly, glossy, lighter in color, and progressively uncombable. The hair growth rate can range from slow to normal, and the condition improves with age. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 3 Ca(2+) cations per subunit. Binds 1 Ca(2+) as a zymogen, and binds 2 more Ca(2+) cations, or other divalent metal cations, after proteolytic processing.

Similarity. Belongs to the transglutaminase superfamily. Transglutaminase family.

RefSeq proteins (1): NP_003236* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001102	Transglutaminase_N	Domain
IPR002931	Transglutaminase-like	Domain
IPR008958	Transglutaminase_C	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR013808	Transglutaminase_AS	Active_site
IPR014756	Ig_E-set	Homologous_superfamily
IPR023608	Transglutaminase_animal	Family
IPR036238	Transglutaminase_C_sf	Homologous_superfamily
IPR036985	Transglutaminase-like_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050779	Transglutaminase	Family

Pfam: PF00868, PF00927, PF01841

Enzyme classification (BRENDA):

• EC 2.3.2.13 — protein-glutamine gamma-glutamyltransferase (BRENDA: 68 organisms, 476 substrates, 772 inhibitors, 122 Km, 49 kcat entries)

Substrate kinetics (BRENDA)

60 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PUTRESCINE	0.035–9.63	13
L-LYSINE	2.9–15.8	6
N-CBZ-GLN-GLY	12.83–59.5	5
HYDROXYLAMINE	1.37–61.9	4
NALPHA-BENZYLOXYCARBONYL-L-GLN-GLY	11.2–30	4
CASEIN	0.006–0.012	3
CBZ-GLN-GLY	0.0169–5.9	3
CBZ-GLN-GLY-OH	3.53–8.55	3
METHYLAMINE	0.024–0.061	3
MONODANSYLCADAVERINE	0.01–0.034	3
N-CARBOXYBENZOYL-L-GLUTAMINYL-GLYCINE	0.0547–69.4	3
PENTYLAMINE	0.0029–0.0203	3
Z-GLN-GLY	1.8–11.6	3
ACETYL-ALPHAS1-CASEIN	0.0029–0.0032	2
GTP	0.0044–0.01	2

Catalyzed reactions (Rhea), 1 shown:

• L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N(6)-5-L-glutamyl-[protein] + NH4(+) (RHEA:54816)

UniProt features (100 total): strand 42, helix 15, binding site 14, turn 8, sequence variant 6, sequence conflict 5, modified residue 3, active site 3, chain 2, initiator methionine 1, site 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8OXW	X-RAY DIFFRACTION	1.7
8OXV	X-RAY DIFFRACTION	1.8
8OXY	X-RAY DIFFRACTION	2
1L9M	X-RAY DIFFRACTION	2.1
1L9N	X-RAY DIFFRACTION	2.1
1NUG	X-RAY DIFFRACTION	2.4
8OXX	X-RAY DIFFRACTION	2.5
1NUD	X-RAY DIFFRACTION	2.7
1NUF	X-RAY DIFFRACTION	2.7
8RMX	X-RAY DIFFRACTION	2.8
8RMY	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08188-F1	96.08	0.95

Antibody-complex structures (SAbDab): 6 — 8OXV, 8OXW, 8OXX, 8OXY, 8RMX, 8RMY

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): 467–468 (cleavage; by ctsl); 273; 331; 354

Ligand- & substrate-binding residues (14): 230; 302; 304; 306; 308; 325; 394; 416; 444; 449; 222; 225 …

Post-translational modifications (3): 2, 111, 112

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 143 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPIDERMIS_MORPHOGENESIS, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_PEPTIDE_CROSS_LINKING, HUMMERICH_BENIGN_SKIN_TUMOR_UP, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GERY_CEBP_TARGETS, NKX62_Q2, SYED_ESTRADIOL_RESPONSE, OCT1_07, TGANTCA_AP1_C

GO Biological Process (5): peptide cross-linking (GO:0018149), keratinocyte differentiation (GO:0030216), hair follicle morphogenesis (GO:0031069), keratinization (GO:0031424), protein modification process (GO:0036211)

GO Molecular Function (8): protein-glutamine gamma-glutamyltransferase activity (GO:0003810), catalytic activity (GO:0003824), structural molecule activity (GO:0005198), calcium ion binding (GO:0005509), acyltransferase activity (GO:0016746), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), extrinsic component of cytoplasmic side of plasma membrane (GO:0031234), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
molecular_function	2
protein modification process	1
epidermal cell differentiation	1
skin development	1
hair follicle development	1
anatomical structure morphogenesis	1
hair cycle process	1
epidermis morphogenesis	1
keratinocyte differentiation	1
multicellular organismal process	1
protein metabolic process	1
macromolecule modification	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
metal ion binding	1
transferase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasmic side of plasma membrane	1
extrinsic component of plasma membrane	1
cellular_component	1
extracellular vesicle	1

Protein interactions and networks

STRING

962 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGM3	LORICRIN	P23490	899
TGM3	CST6	Q15828	866
TGM3	LGMN	Q99538	826
TGM3	SBSN	Q6UWP8	819
TGM3	IVL	P07476	741
TGM3	FLG2	Q5D862	705
TGM3	CDSN	Q15517	703
TGM3	CRNN	Q9UBG3	698
TGM3	FLG	P20930	680
TGM3	CASP14	P31944	608
TGM3	CNFN	Q9BYD5	604
TGM3	KRTDAP	P60985	582
TGM3	SPRR3	Q9UBC9	554
TGM3	BLMH	Q13867	542
TGM3	CALML5	Q9NZT1	533

IntAct

142 interactions, top by confidence:

A	B	Type	Score
FANCG	FANCA	psi-mi:“MI:0914”(association)	0.960
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ANXA9	PPL	psi-mi:“MI:0914”(association)	0.660
IFT88	IFT56	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
POLR2L	RCCD1	psi-mi:“MI:0914”(association)	0.640
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
CFAP298	PEX7	psi-mi:“MI:0914”(association)	0.620
TGM3	PPME1	psi-mi:“MI:0915”(physical association)	0.590
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
DNAAF19	KLK10	psi-mi:“MI:0914”(association)	0.530
CCDC51	TGM5	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
ARAF	BAG2	psi-mi:“MI:0914”(association)	0.530
ZNF224	LRP4	psi-mi:“MI:0914”(association)	0.530
PHAF1	PSMG1	psi-mi:“MI:0914”(association)	0.530
INPP5A	RCCD1	psi-mi:“MI:0914”(association)	0.530
TGM3		psi-mi:“MI:0414”(enzymatic reaction)	0.440
	TGM3	psi-mi:“MI:0414”(enzymatic reaction)	0.440

BioGRID (175): TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), PPME1 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS), TGM3 (Affinity Capture-MS)

ESM2 similar proteins: A0A481NSZ4, A0JPN3, A2BGH0, A6QP57, D4A5U3, G3HIK4, O02668, O76879, P11597, P17213, P17453, P17454, P18428, P19823, P19827, P22687, P47896, P55058, P55065, P59826, P59827, P97278, Q05701, Q05704, Q08188, Q08189, Q0VCM5, Q10011, Q24764, Q28739, Q29052, Q2TBI0, Q61114, Q61702, Q61703, Q61805, Q63313, Q67E05, Q6AXU0, Q80ZU7

Diamond homologs: A6QP57, D4A5U3, O08619, O43548, O46510, O95932, P00488, P08587, P16452, P21980, P21981, P22735, P22758, P23606, P49221, P51176, P52181, P52183, Q01841, Q05187, Q08188, Q08189, Q8BH61, Q8BZH1, Q96PF1, Q99041, Q9D7I9, Q9GLK0, Q9JLF6, Q9WVJ6, P49222, P12260

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	123
Likely benign	21
Benign	15

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
374840	NM_003245.4(TGM3):c.1351C>T (p.Gln451Ter)	Pathogenic

SpliceAI

2397 predictions. Top by Δscore:

Variant	Effect	Δscore
20:2309826:CACAG:C	donor_loss	1.0000
20:2309828:CAGG:C	donor_loss	1.0000
20:2309831:G:GC	donor_loss	1.0000
20:2309832:T:A	donor_loss	1.0000
20:2310173:GACA:G	acceptor_loss	1.0000
20:2310175:CAG:C	acceptor_loss	1.0000
20:2310176:AG:A	acceptor_gain	1.0000
20:2310176:AGG:A	acceptor_gain	1.0000
20:2310177:G:A	acceptor_loss	1.0000
20:2310177:GG:G	acceptor_gain	1.0000
20:2310177:GGG:G	acceptor_gain	1.0000
20:2310383:G:GT	donor_gain	1.0000
20:2310383:G:T	donor_gain	1.0000
20:2311009:A:AG	acceptor_gain	1.0000
20:2311010:G:GG	acceptor_gain	1.0000
20:2312896:A:AG	acceptor_gain	1.0000
20:2312897:G:GG	acceptor_gain	1.0000
20:2312897:GTTT:G	acceptor_gain	1.0000
20:2313023:CATGG:C	donor_loss	1.0000
20:2313024:ATGGT:A	donor_loss	1.0000
20:2313025:TG:T	donor_gain	1.0000
20:2313025:TGGT:T	donor_loss	1.0000
20:2313026:GG:G	donor_gain	1.0000
20:2313027:G:GG	donor_gain	1.0000
20:2313027:GTGA:G	donor_loss	1.0000
20:2313028:TGAG:T	donor_loss	1.0000
20:2313029:GAGTA:G	donor_loss	1.0000
20:2313030:AGTAA:A	donor_loss	1.0000
20:2317100:T:A	acceptor_gain	1.0000
20:2328204:C:CA	acceptor_gain	1.0000

AlphaMissense

4599 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:2311115:T:A	W176R	0.999
20:2311115:T:C	W176R	0.999
20:2317155:A:C	S253R	0.999
20:2317157:C:A	S253R	0.999
20:2317157:C:G	S253R	0.999
20:2317217:C:G	C273W	0.999
20:2325853:T:C	F330L	0.999
20:2325855:C:A	F330L	0.999
20:2325855:C:G	F330L	0.999
20:2325856:C:G	H331D	0.999
20:2325862:T:A	W333R	0.999
20:2325862:T:C	W333R	0.999
20:2311117:G:C	W176C	0.998
20:2311117:G:T	W176C	0.998
20:2317109:G:C	W237C	0.998
20:2317109:G:T	W237C	0.998
20:2317210:G:A	G271D	0.998
20:2317215:T:C	C273R	0.998
20:2317218:T:A	W274R	0.998
20:2317218:T:C	W274R	0.998
20:2317220:G:C	W274C	0.998
20:2317220:G:T	W274C	0.998
20:2317224:T:C	F276L	0.998
20:2317226:T:A	F276L	0.998
20:2317226:T:G	F276L	0.998
20:2317228:C:A	A277D	0.998
20:2317386:C:T	T295I	0.998
20:2317391:T:C	F297L	0.998
20:2317393:C:A	F297L	0.998
20:2317393:C:G	F297L	0.998

dbSNP variants (sampled 300 via entrez): RS1000009856 (20:2329637 A>T), RS1000018224 (20:2302622 C>T), RS1000094939 (20:2325163 C>G), RS1000164159 (20:2334484 G>A,C), RS1000185950 (20:2297477 G>A), RS1000201076 (20:2301209 C>A,T), RS1000315734 (20:2303388 G>A), RS1000318774 (20:2296780 G>A), RS1000346461 (20:2334912 T>C), RS1000468432 (20:2334264 G>A), RS1000558798 (20:2326342 G>T), RS1000702036 (20:2337889 A>G), RS1000760551 (20:2295928 C>G,T), RS1000769669 (20:2339307 G>T), RS1000906591 (20:2333556 A>G)

Disease associations

OMIM: gene MIM:600238 | disease phenotypes: MIM:617251

GenCC curated gene-disease

Disease	Classification	Inheritance
uncombable hair syndrome 2	Moderate	Autosomal recessive
uncombable hair syndrome	Supportive	Autosomal recessive

Mondo (2): uncombable hair syndrome 2 (MONDO:0014989), uncombable hair syndrome (MONDO:0008621)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001118	Juvenile cataract
HP:0001595	Abnormal hair morphology
HP:0002208	Coarse hair
HP:0002224	Woolly hair
HP:0002232	Patchy alopecia
HP:0002235	Pili canaliculi
HP:0002552	Trichodysplasia
HP:0003593	Infantile onset
HP:0011364	White hair
HP:0030056	Uncombable hair

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST002331_1	Basal cell carcinoma	6.000000e-17
GCST002331_11	Basal cell carcinoma	3.000000e-09
GCST002740_36	Inflammatory skin disease	5.000000e-06
GCST002842_8	Basal cell carcinoma	2.000000e-13
GCST003726_4	Basal cell carcinoma	8.000000e-33
GCST005896_12	Non-melanoma skin cancer	1.000000e-18
GCST008870_43	Keratinocyte cancer (MTAG)	1.000000e-12
GCST008870_80	Keratinocyte cancer (MTAG)	6.000000e-66
GCST008871_63	Basal cell carcinoma	3.000000e-81
GCST009391_1075	Metabolite levels	4.000000e-06
GCST009391_2112	Metabolite levels	3.000000e-06
GCST009391_2137	Metabolite levels	3.000000e-07
GCST90013410_62	Basal cell carcinoma	5.000000e-20
GCST90013410_63	Basal cell carcinoma	1.000000e-59
GCST90013410_64	Basal cell carcinoma	1.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009260	non-melanoma skin carcinoma
EFO:0010176	keratinocyte carcinoma
EFO:0010365	lysophosphatidylcholine 22:6 measurement
EFO:0010381	phosphatidylcholine 36:3 measurement
EFO:0010384	phosphatidylcholine 38:2 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536939	Uncombable hair syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3363 (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: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

Binding affinities (BindingDB)

5 measured of 17 human assays (17 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]-2-bromo-acetamide (6e)	IC50	3.9 nM
N-[2-[4-(adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]prop-2-enamide (3e)	IC50	125 nM
[2-[[2-[4-(1-Adamantylmethoxycarbonyl)piperazin-1-yl]-2-oxo-ethyl]amino]-2-oxoethyl]-dimethyl-sulfonium bromide (1f)	IC50	775 nM
[2-[[2-[4-(Adamantane-1-carbonyl)piperazin-1-yl]-2-oxo-ethyl]amino]-2-oxo-ethyl]-dimethyl-sulfonium bromide (1e)	IC50	889 nM
1-Adamantylmethyl 4-[2-(prop-2-enoylamino)acetyl]piperazine-1-carboxylate (3f)	IC50	1620 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 8 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	IC50	11	nM	CHEMBL2086889
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 117 total; 2 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
1-ethyl-3-(4-methoxyphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	683886: Inhibition of thrombin activated human TG3 by fluorescent transamidation assay	ic50	0.0110	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178721: Inhibition of TGM3 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases reaction, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	2
Aflatoxin B1	increases methylation	2
propionaldehyde	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases reaction, increases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	affects cotreatment, decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression	1
Nickel	increases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1
Asbestos, Crocidolite	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1
Sirolimus	decreases expression	1
Particulate Matter	increases expression	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2091159	Binding	Inhibition of thrombin activated human TG3 by fluorescent transamidation assay	Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington’s disease. — J Med Chem

Clinical trials (associated diseases)

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