TGIF1

Summary

TGIF1 (TGFB induced factor homeobox 1, HGNC:11776) is a protein-coding gene on chromosome 18p11.31, encoding Homeobox protein TGIF1 (Q15583). Binds to a retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII-RXRE). It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the three-amino acid loop extension (TALE) superclass of atypical homeodomains. TALE homeobox proteins are highly conserved transcription regulators. This particular homeodomain binds to a previously characterized retinoid X receptor responsive element from the cellular retinol-binding protein II promoter. In addition to its role in inhibiting 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element, the protein is an active transcriptional co-repressor of SMAD2 and may participate in the transmission of nuclear signals during development and in the adult. Mutations in this gene are associated with holoprosencephaly type 4, which is a structural anomaly of the brain. Alternative splicing has been observed at this locus and multiple splice variants encoding distinct isoforms are described.

Source: NCBI Gene 7050 — RefSeq curated summary.

At a glance

• Gene–disease (curated): holoprosencephaly 4 (Definitive, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 187 total — 4 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 127
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_003244

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11776
Approved symbol	TGIF1
Name	TGFB induced factor homeobox 1
Location	18p11.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000177426
Ensembl biotype	protein_coding
OMIM	602630
Entrez	7050

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 25 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000330513, ENST00000343820, ENST00000345133, ENST00000400167, ENST00000401449, ENST00000405385, ENST00000407501, ENST00000472042, ENST00000546979, ENST00000547233, ENST00000548489, ENST00000549253, ENST00000549468, ENST00000549546, ENST00000549780, ENST00000550958, ENST00000551333, ENST00000551402, ENST00000551541, ENST00000551557, ENST00000552383, ENST00000577543, ENST00000618001, ENST00000870197, ENST00000870198, ENST00000870199, ENST00000927544

RefSeq mRNA: 13 — MANE Select: NM_003244 NM_001278682, NM_001278684, NM_001278686, NM_001374396, NM_001374397, NM_003244, NM_170695, NM_173207, NM_173208, NM_173209, NM_173210, NM_173211, NM_174886

CCDS: CCDS11832, CCDS11833, CCDS11835

Canonical transcript exons

ENST00000343820 — 3 exons

Exon	Start	End
ENSE00002409832	3450172	3450505
ENSE00003556547	3456354	3456580
ENSE00003900360	3457365	3459978

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 97.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.5765 / max 523.7721, expressed in 1810 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169184	39.7416	1785
169172	2.4862	864
169189	2.2366	1145
169185	1.9856	1085
169182	1.8250	857
169178	1.4868	759
169171	1.4441	587
169176	1.3894	424
169173	1.2922	493
169183	1.2492	788

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	97.31	gold quality
gall bladder	UBERON:0002110	96.86	gold quality
ventricular zone	UBERON:0003053	96.84	gold quality
corpus epididymis	UBERON:0004359	96.81	gold quality
rectum	UBERON:0001052	96.34	gold quality
mucosa of stomach	UBERON:0001199	96.03	gold quality
right uterine tube	UBERON:0001302	95.82	gold quality
left uterine tube	UBERON:0001303	95.66	gold quality
cartilage tissue	UBERON:0002418	95.65	gold quality
skin of abdomen	UBERON:0001416	95.26	gold quality
caput epididymis	UBERON:0004358	95.09	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.02	gold quality
minor salivary gland	UBERON:0001830	94.59	gold quality
skin of leg	UBERON:0001511	94.48	gold quality
left ovary	UBERON:0002119	94.34	gold quality
upper lobe of left lung	UBERON:0008952	94.34	gold quality
transverse colon	UBERON:0001157	94.28	gold quality
endometrium	UBERON:0001295	94.14	gold quality
right ovary	UBERON:0002118	94.00	gold quality
endocervix	UBERON:0000458	93.89	gold quality
body of uterus	UBERON:0009853	93.76	gold quality
upper lobe of lung	UBERON:0008948	93.74	gold quality
omental fat pad	UBERON:0010414	93.71	gold quality
metanephros cortex	UBERON:0010533	93.71	gold quality
peritoneum	UBERON:0002358	93.69	gold quality
body of stomach	UBERON:0001161	93.68	gold quality
right lung	UBERON:0002167	93.62	gold quality
tibial nerve	UBERON:0001323	93.52	gold quality
tibial artery	UBERON:0007610	93.50	gold quality
popliteal artery	UBERON:0002250	93.49	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	19.00
E-GEOD-93593	yes	14.72
E-MTAB-8271	yes	7.89
E-MTAB-10596	no	357.93
E-GEOD-36552	no	343.22
E-MTAB-6524	no	342.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
ACTG2	Repression
CDKN1A	Unknown
DRD1	Repression
ELAVL1
ELN	Repression
FSHB	Unknown
HTT
KRAS
NODAL	Unknown
RARB
SERPINE1	Repression
SOX3	Repression
TGFB1	Repression

JASPAR motifs

Motif	Name	Family
MA0796.1	TGIF1	TALE-type homeo domain factors

JASPAR matrix evidence (PMIDs): PMID:8537382

Upstream regulators (CollecTRI, top): CTNNB1, HDAC4, NR1H3, TCF7L2

miRNA regulators (miRDB)

54 targeting TGIF1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-5700	99.64	69.88	2280

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• molecular analysis of holoprosencephaly identified a novel heterozygous missense TGIF mutation (PMID:11810641)
• The first nonsense mutation and also a novel missense mutation identified in tgif gene is associated with holoprosencephaly (PMID:12522553)
• TGF-beta affects the gene expression regulation of this protein in normal and tumor cell lines. (PMID:12593671)
• TGIF is a probable candidate gene for high myopia. (PMID:12601022)
• Mutation analysis of the encoded TGIF gene for MYP2 autosomal dominant high myopia did not identify sequence alterations associated with the disease phenotype. (PMID:15223781)
• Hypermethylation of cellular retinol-binding protein 1 is associated with gastric carcinogenesis (PMID:16134180)
• The interaction of TGIF with cPML through c-Jun may negatively regulate TGF-beta signaling through controlling the localization of cPML and, consequently, the assembly of the cPML-SARA complex. (PMID:16916642)
• Of the eleven sequence variations in TGIF, all but four can be demonstrated to be functionally abnormal, associated with holoprosencephaly. (PMID:16962354)
• We found no statistical association between any of the 13 SNPs located on the TGIF gene and high myopia in Japanese subjects. (PMID:17048038)
• results reveal an important mechanism for the degradation of TGIF through the ubiquitin-proteasome pathway, whose deregulation might contribute to the development of human holoprosencephaly (PMID:17158784)
• This results point to the possible involvement of TGIF in the pathophysiology of psychotic disorders in the CVCR population. (PMID:17440433)
• A Brazilian boy with lobar holoprosencephaly has a K44N mutation in the TGIF gene. (PMID:17825514)
• Findings of this study suggest that the TGIF gene is unlikely to play a major role in either ocular biometric measures or refraction in a Caucasian population. (PMID:18172074)
• TGIF is essential for EGF-mediated downregulation of tropoelastin expression (PMID:18441095)
• A detailed description of the TGIF locus characterizing 12 TGIF splice isoforms. (PMID:18455519)
• The study does not support the association of high myopia with alleles of rs2229336 in TGIF, rs3759223 in lumican, rs1982073 in TGFB1, and rs3735520 in HGF. (PMID:19060265)
• TGIF is a potential repressor of TGF-beta pathways in myometrial cells. (PMID:19524896)
• Data suggest that transforming growth-interacting factor (TGIF) has an important role myelopoiesis and may regulate the balance between proliferation and differentiation. (PMID:19699159)
• Data show that activation of TNF-alpha signaling induced the association of TGIF with Itch/AIP4, resulting in increased accessibility of cFlip(L) for association and ubiquitination by Itch/AIP4. (PMID:20064471)
• The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH and significantly more in SIX3. For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports (PMID:20531442)
• Cancer cell lines with inactivating mutations in Fbxw7 show enhanced levels of TGIF1 and attenuated TGFbeta-dependent signaling (PMID:20622901)
• TGIF1 transcript signals were frequently intense in normal tissue, and generally weak in oral squamous cell carcinoma (OSCC), and stronger transcript signals in well-differentiated areas of OSCC when compared with poorly differentiated ones. (PMID:21237437)
• The Smad corepressor transforming growth interacting factor was found to have flow-dependent nuclear localization (PMID:21490324)
• Longer survival was associated with hypomethylation at specific CpG sites (e.g. GREB1, TGIF and TOB1) and hypermethylation in other genes (e.g. TMCO5, PTPRN and GUCY2C). (PMID:21577013)
• There was a positive correlation between the severity of the brain malformation and facial features for SHH, SIX3, and TGIF, but no such correlation was found for ZIC2 mutations. (PMID:21940735)
• TGIF (TG-interacting factor) is an additional TALE superfamily member involved in the regulation of human SOX3 gene expression (PMID:22293114)
• Mutations in TGIF is associated with holoprosencephaly. (PMID:22310223)
• Exclusion of mutations in TGIF gene in patients with the syndrome of frontonasal dysgenesis, callosal agenesis, basal encephalocele, and eye anomalies (PMID:22496059)
• TGIF can promote cellular migration/invasion activity of urothelial carcinoma cells. (PMID:22728270)
• TGIF contributes to the progression of urothelial carcinoma via the phosphatidylinositol 3-kinase-AKT pathway. (PMID:22771156)
• TGIF1 plays a role in TNF-alpha- and radiation-induced inflammation and it could be a target in limiting this event in the vascular compartment (PMID:22995913)
• biochemical analysis of how to overcome TALE DNA binding domain sensitivity to cytosine methylation (PMID:23019344)
• 2 mutations in the holoprosencephaly (HPE)-related genes were detected (c.799 C>T, p.Q267X in TGIF gene and c.1279G>A, p.G427R in SHH gene) in 2 patients with pituitary stalk interruption syndrome (PSIS); data suggest HPE-related gene mutations are implicated in the etiolog of isolated pituitary defects (PMID:23476075)
• Data demonstrate that homeobox gene TGIF-1 is a potential up-stream regulator of trophoblast differentiation and the altered TGIF-1 expression may contribute to aberrant villous trophoblast differentiation in FGR. (PMID:23761267)
• Alternative splicing of TGIF1 is deregulated in OSCC, with overexpression of some splicing variants, especially TGIF1v8, which is associated with advanced stages of OSCC. (PMID:24119525)
• TGIF1 is a relevant candidate gene with potential to contribute in the genesis of high myopia. (PMID:24215395)
• TG-interacting factor 1 (Tgif1) is an important repressor of SOAT2 gene expression. (PMID:24478032)
• TGIF1 has a role as a negative regulator of MLL-rearranged acute myeloid leukemia (PMID:25349154)
• we suggest that TGIF plays an important role in low-dose arsenic-induced malignant transformation of HaCaT cells, which is regulated by c-Src/EGFR/AKT/FOXO3A pathway and redox signaling. (PMID:25537191)
• TG-interacting factor transcriptionally induced by AKT/FOXO3A is a negative regulator that antagonizes arsenic trioxide-induced cancer cell apoptosis. (PMID:25791921)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgif1	ENSDARG00000059337
mus_musculus	Tgif1	ENSMUSG00000047407
rattus_norvegicus	Tgif1	ENSRNOG00000015906
drosophila_melanogaster	exd	FBGN0000611
drosophila_melanogaster	hth	FBGN0001235
drosophila_melanogaster	vis	FBGN0033748
drosophila_melanogaster	achi	FBGN0033749
caenorhabditis_elegans		WBGENE00000443
caenorhabditis_elegans		WBGENE00006796
caenorhabditis_elegans		WBGENE00017690

Paralogs (13): MEIS3 (ENSG00000105419), PBX4 (ENSG00000105717), TGIF2 (ENSG00000118707), MEIS2 (ENSG00000134138), MEIS1 (ENSG00000143995), TGIF2LX (ENSG00000153779), PKNOX1 (ENSG00000160199), PKNOX2 (ENSG00000165495), PBX3 (ENSG00000167081), TGIF2LY (ENSG00000176679), PBX1 (ENSG00000185630), MEIS3P2 (ENSG00000188013), PBX2 (ENSG00000204304)

Protein

Protein identifiers

Homeobox protein TGIF1 — Q15583 (reviewed: Q15583)

Alternative names: 5’-TG-3’-interacting factor 1

All UniProt accessions (11): Q15583, F8VUY0, F8VVS9, F8VW34, F8VWK5, F8VX54, F8VXG3, F8VYL4, F8VZH2, F8W1J9, J3KS32

UniProt curated annotations — full annotation on UniProt →

Function. Binds to a retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII-RXRE). Inhibits the 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element. Active transcriptional corepressor of SMAD2. Links the nodal signaling pathway to the bifurcation of the forebrain and the establishment of ventral midline structures. May participate in the transmission of nuclear signals during development and in the adult, as illustrated by the down-modulation of the RXR alpha activities.

Subunit / interactions. Interacts with SMAD2. Interacts with CTBP, SMAD3 and HDAC1.

Subcellular location. Nucleus.

Disease relevance. Holoprosencephaly 4 (HPE4) [MIM:142946] 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. HPE4 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TALE/TGIF homeobox family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q15583-1	1	yes
Q15583-2	2
Q15583-3	3
Q15583-4	4

RefSeq proteins (13): NP_001265611, NP_001265613, NP_001265615, NP_001361325, NP_001361326, NP_003235, NP_733796, NP_775299, NP_775300, NP_775301, NP_775302, NP_775303, NP_777480 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR008422	KN_HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR050224	TALE_homeobox	Family

Pfam: PF05920

UniProt features (26 total): sequence variant 8, splice variant 5, region of interest 4, helix 4, chain 1, DNA-binding region 1, sequence conflict 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6FQP	X-RAY DIFFRACTION	2.42
6FQQ	X-RAY DIFFRACTION	3.25
2LK2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15583-F1	59.18	0.20

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-162582	Signal Transduction
R-HSA-170834	Signaling by TGF-beta Receptor Complex
R-HSA-212436	Generic Transcription Pathway
R-HSA-2173793	Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 747 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, BROWNE_HCMV_INFECTION_6HR_DN, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, MYOGENIN_Q6, TGCGCANK_UNKNOWN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_FIBROBLAST_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_REGULATION_OF_RETINOIC_ACID_RECEPTOR_SIGNALING_PATHWAY, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), neural tube closure (GO:0001843), determination of left/right symmetry (GO:0007368), negative regulation of cell population proliferation (GO:0008285), response to xenobiotic stimulus (GO:0009410), dorsal/ventral pattern formation (GO:0009953), regulation of gastrulation (GO:0010470), negative regulation of gene expression (GO:0010629), amacrine cell differentiation (GO:0035881), nodal signaling pathway (GO:0038092), fibroblast proliferation (GO:0048144), positive regulation of fibroblast proliferation (GO:0048146), negative regulation of retinoic acid receptor signaling pathway (GO:0048387), cellular response to growth factor stimulus (GO:0071363), positive regulation of amacrine cell differentiation (GO:1902871), regulation of DNA-templated transcription (GO:0006355), cell population proliferation (GO:0008283), neuron differentiation (GO:0030182), retina development in camera-type eye (GO:0060041)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), co-SMAD binding (GO:0070410), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleoplasm (GO:0005654), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	2
Signaling by TGFB family members	1
RNA Polymerase II Transcription	1
Signaling by TGF-beta Receptor Complex	1
Generic Transcription Pathway	1
Gene expression (Transcription)	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
cell population proliferation	2
regulation of gene expression	2
binding	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
primary neural tube formation	1
tube closure	1
determination of bilateral symmetry	1
left/right pattern formation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
response to chemical	1
regionalization	1
gastrulation	1
regulation of anatomical structure morphogenesis	1
regulation of embryonic development	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
neural retina development	1
central nervous system neuron differentiation	1
activin receptor signaling pathway	1
positive regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
retinoic acid receptor signaling pathway	1
regulation of retinoic acid receptor signaling pathway	1
negative regulation of intracellular signal transduction	1
response to growth factor	1
cellular response to endogenous stimulus	1
amacrine cell differentiation	1
positive regulation of neuron differentiation	1
regulation of amacrine cell differentiation	1
DNA-templated transcription	1
regulation of RNA biosynthetic process	1
cellular process	1
cell differentiation	1
generation of neurons	1

Protein interactions and networks

STRING

1354 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGIF1	SMAD2	Q15796	845
TGIF1	RARA	P10276	682
TGIF1	SIX3	O95343	666
TGIF1	SKIL	P12756	640
TGIF1	CTBP1	Q13363	607
TGIF1	SMAD4	Q13485	569
TGIF1	ZIC2	O95409	532
TGIF1	CTBP2	P56545	497
TGIF1	RXRA	P19793	488
TGIF1	INHBA	P08476	485
TGIF1	PPARG	P37231	477
TGIF1	AR	P10275	467
TGIF1	BCL6	P41182	465
TGIF1	CDON	Q4KMG0	449
TGIF1	OSR2	Q8N2R0	443
TGIF1	IRF7	Q92985	443

IntAct

76 interactions, top by confidence:

A	B	Type	Score
TGIF1	CTBP2	psi-mi:“MI:0915”(physical association)	0.740
CTBP2	TGIF1	psi-mi:“MI:0915”(physical association)	0.740
MDFI	TGIF1	psi-mi:“MI:0915”(physical association)	0.670
TGIF1	MDFI	psi-mi:“MI:0915”(physical association)	0.670
COMMD3	VPS26C	psi-mi:“MI:0914”(association)	0.640
TGIF1	LGALS8	psi-mi:“MI:0915”(physical association)	0.600
LGALS8	TGIF1	psi-mi:“MI:0915”(physical association)	0.600
TGIF1	LGALS8	psi-mi:“MI:0403”(colocalization)	0.600
LGALS8	TGIF1	psi-mi:“MI:0403”(colocalization)	0.600
TGIF1	AXIN2	psi-mi:“MI:0915”(physical association)	0.570
AXIN2	TGIF1	psi-mi:“MI:0915”(physical association)	0.570
TGIF1	CTBP1	psi-mi:“MI:0915”(physical association)	0.560
CTBP1	TGIF1	psi-mi:“MI:0915”(physical association)	0.560
FMR1	TGIF1	psi-mi:“MI:0915”(physical association)	0.560
SMAD3	TGIF1	psi-mi:“MI:0915”(physical association)	0.560
TGIF1	PNP	psi-mi:“MI:0915”(physical association)	0.560
TGIF1	PLK1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (52): TGIF1 (Two-hybrid), TGIF1 (Two-hybrid), TGIF1 (Two-hybrid), TGIF1 (Two-hybrid), TGIF1 (Two-hybrid), TGIF1 (Two-hybrid), TGIF1 (Two-hybrid), CTBP1 (Two-hybrid), CTBP2 (Two-hybrid), MKKS (Affinity Capture-MS), SDAD1 (Affinity Capture-MS), STK16 (Affinity Capture-MS), CTBP1 (Affinity Capture-Western), CTBP1 (Two-hybrid), TGIF1 (Affinity Capture-Western)

ESM2 similar proteins: A0A1L8I316, A6NCN8, A6NFA0, A6NFR6, A6NJB7, A6NL46, A6QP24, A6QQS3, A8MUI8, A8MX80, B2RW88, B7ZNG4, D3ZUE1, Q05860, Q0P670, Q0VD86, Q12815, Q15583, Q1LZE2, Q1RN00, Q2HR82, Q32LI3, Q32LN6, Q3B8N5, Q5BMD4, Q5DU28, Q5IS58, Q5NCP0, Q5SSG4, Q5SSZ7, Q66H53, Q68DA7, Q68DV7, Q6PE65, Q7TPN9, Q80U22, Q80VY2, Q80YD3, Q8BII1, Q8IZ16

Diamond homologs: A1YGI6, A6NDR6, A8K0S8, A8WL06, B7ZRT8, O00470, O04136, O14770, O22300, O42261, O46339, O65685, O70477, P41779, P41817, P46606, P48000, P48001, P48002, P48731, P53147, P54269, P55347, P56659, P56660, P56664, P56665, P56669, P70284, P78412, P78413, P78414, P78415, P79937, P81067, P81068, P97367, P97368, Q0E3C3, Q0J6N4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TGIF1	up-regulates	WWP1	binding
ITCH	“up-regulates activity”	TGIF1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression	6	14.3×	9e-04
negative regulation of cell population proliferation	7	10.2×	9e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — COADREAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	6
Uncertain significance	74
Likely benign	41
Benign	35

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
2671956	NM_003244.4(TGIF1):c.257del (p.Phe86fs)	Pathogenic
533431	NM_003244.4(TGIF1):c.268C>T (p.Arg90Cys)	Pathogenic
6980	NM_003244.4(TGIF1):c.188C>G (p.Pro63Arg)	Pathogenic
6983	NM_003244.4(TGIF1):c.16+1651C>G	Pathogenic
2582647	NM_003244.4(TGIF1):c.214del (p.Ser72fs)	Likely pathogenic
279908	NM_003244.4(TGIF1):c.778del (p.Arg260fs)	Likely pathogenic
3024102	NM_003244.4(TGIF1):c.16+1805del	Likely pathogenic
3026744	NM_003244.4(TGIF1):c.319C>T (p.Gln107Ter)	Likely pathogenic
3378040	NM_003244.4(TGIF1):c.177C>A (p.Tyr59Ter)	Likely pathogenic
546555	NM_003244.4(TGIF1):c.708dup (p.Pro237fs)	Likely pathogenic

SpliceAI

716 predictions. Top by Δscore:

Variant	Effect	Δscore
18:3456352:A:AG	acceptor_gain	1.0000
18:3456352:AG:A	acceptor_gain	1.0000
18:3456353:G:GA	acceptor_gain	1.0000
18:3456353:GG:G	acceptor_gain	1.0000
18:3456353:GGT:G	acceptor_gain	1.0000
18:3456353:GGTA:G	acceptor_gain	1.0000
18:3456353:GGTAT:G	acceptor_gain	1.0000
18:3456576:TACAG:T	donor_loss	1.0000
18:3456577:ACAG:A	donor_loss	1.0000
18:3456578:CAG:C	donor_loss	1.0000
18:3456579:AG:A	donor_loss	1.0000
18:3456580:G:GC	donor_loss	1.0000
18:3456581:GT:G	donor_loss	1.0000
18:3456582:T:A	donor_loss	1.0000
18:3450067:G:GT	donor_gain	0.9900
18:3450068:A:T	donor_gain	0.9800
18:3456348:TCCTA:T	acceptor_gain	0.9800
18:3456349:CCTAG:C	acceptor_gain	0.9800
18:3456350:CTAGG:C	acceptor_gain	0.9800
18:3456351:TAG:T	acceptor_gain	0.9800
18:3456352:AGG:A	acceptor_gain	0.9800
18:3456353:G:C	acceptor_gain	0.9800
18:3456592:GAGC:G	donor_gain	0.9800
18:3457690:A:AG	acceptor_gain	0.9800
18:3457691:G:GG	acceptor_gain	0.9800
18:3456439:C:T	donor_gain	0.9700
18:3457690:AGTC:A	acceptor_gain	0.9700
18:3457691:GTCG:G	acceptor_gain	0.9700
18:3455261:G:GA	donor_gain	0.9600
18:3456583:A:C	donor_loss	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000017863 (18:3450759 C>T), RS1000150063 (18:3434487 G>A,C), RS1000190827 (18:3431986 G>T), RS1000281665 (18:3437136 C>T), RS1000300844 (18:3411807 A>G), RS1000301642 (18:3426495 C>T), RS1000591312 (18:3411560 A>G), RS1000595874 (18:3449985 C>G), RS1000804205 (18:3437951 G>C), RS1000804855 (18:3453733 C>G,T), RS1000814850 (18:3432116 A>G), RS1000888012 (18:3437646 C>T), RS1000994788 (18:3417727 A>C), RS1001014137 (18:3454902 G>A), RS1001084178 (18:3445123 A>C)

Disease associations

OMIM: gene MIM:602630 | disease phenotypes: MIM:142946

GenCC curated gene-disease

Disease	Classification	Inheritance
holoprosencephaly 4	Definitive	Autosomal dominant

Mondo (2): disorder of sexual differentiation (MONDO:0002145), holoprosencephaly 4 (MONDO:0007734)

Orphanet (2): Difference of sex development (Orphanet:90771), Holoprosencephaly (Orphanet:2162)

HPO phenotypes

127 total (30 of 127 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:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000322	Short philtrum
HP:0000407	Sensorineural hearing impairment
HP:0000437	Depressed nasal tip
HP:0000446	Narrow nasal bridge
HP:0000453	Choanal atresia
HP:0000457	Depressed nasal ridge
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000601	Hypotelorism
HP:0000612	Iris coloboma
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000736	Short attention span
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002129_13	Periodontitis (DPAL)	5.000000e-06
GCST002408_15	Response to methotrexate in juvenile idiopathic arthritis	5.000000e-06
GCST009391_49	Metabolite levels	2.000000e-06
GCST90002390_547	Mean corpuscular hemoglobin	9.000000e-10
GCST90002392_37	Mean corpuscular volume	5.000000e-09
GCST90002393_615	Monocyte count	1.000000e-10
GCST90002394_419	Monocyte percentage of white cells	2.000000e-15
GCST90002396_649	Mean reticulocyte volume	1.000000e-13
GCST90002397_380	Mean spheric corpuscular volume	7.000000e-09
GCST90002398_315	Neutrophil count	1.000000e-10
GCST90013406_130	Liver enzyme levels (alkaline phosphatase)	3.000000e-12

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0009777	citrulline measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0004833	neutrophil count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
C564180	Holoprosencephaly 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	decreases reaction, increases expression, increases reaction, decreases degradation, affects cotreatment (+3 more)	4
Valproic Acid	decreases expression, increases expression, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression, affects expression	3
Formaldehyde	increases expression	3
sodium arsenite	decreases expression	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression	2
4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline	decreases reaction, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Tretinoin	decreases expression	2
Cyclosporine	increases expression	2
Particulate Matter	increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects expression	1
geraniol	increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
ciglitazone	affects binding, increases expression	1
beta-methylcholine	affects expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
tamibarotene	decreases expression	1

Cellosaurus cell lines

7 cell lines: 3 embryonic stem cell, 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7J6	SEES3-1V human TGIF1, clone1	Embryonic stem cell	Male
CVCL_A7J7	SEES3-1V human TGIF1, clone2	Embryonic stem cell	Male
CVCL_A7J8	SEES3-1V human TGIF1, clone3	Embryonic stem cell	Male
CVCL_D8CD	Ubigene A-549 TGIF1 KO	Cancer cell line	Male
CVCL_D8X2	Ubigene HCT 116 TGIF1 KO	Cancer cell line	Male
CVCL_D9U7	Ubigene HEK293 TGIF1 KO	Transformed cell line	Female
CVCL_E0QX	Ubigene HeLa TGIF1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions