TWIST2

Summary

TWIST2 (twist family bHLH transcription factor 2, HGNC:20670) is a protein-coding gene on chromosome 2q37.3, encoding Twist-related protein 2 (Q8WVJ9). Binds to the E-box consensus sequence 5’-CANNTG-3’ as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C.

The protein encoded by this gene is a basic helix-loop-helix type transcription factor and shares similarity with Twist. This protein may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype during osteoblast development. This gene may be upregulated in certain cancers. Mutations in this gene cause focal facial dermal dysplasia 3, Setleis type. Two transcript variants encoding the same protein have been found.

Source: NCBI Gene 117581 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ablepharon macrostomia syndrome (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 40 total — 7 pathogenic
• Phenotypes (HPO): 130
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Transcription factor: yes — 35 downstream targets (CollecTRI)
• MANE Select transcript: NM_001271893

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20670
Approved symbol	TWIST2
Name	twist family bHLH transcription factor 2
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	DERMO1, Dermo-1, bHLHa39
Ensembl gene	ENSG00000233608
Ensembl biotype	protein_coding
OMIM	607556
Entrez	117581

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000448943, ENST00000612363, ENST00000710607, ENST00000935934, ENST00000941615

RefSeq mRNA: 2 — MANE Select: NM_001271893 NM_001271893, NM_057179

CCDS: CCDS46558

Canonical transcript exons

ENST00000612363 — 2 exons

Exon	Start	End
ENSE00003714010	238909842	238910534
ENSE00003847668	238848085	238848733

Expression profiles

Bgee: expression breadth ubiquitous, 126 present calls, max score 97.63.

FANTOM5 (CAGE): breadth broad, TPM avg 13.8936 / max 285.6531, expressed in 877 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26355	10.1998	840
26356	3.6938	703

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	97.63	gold quality
endocervix	UBERON:0000458	97.15	gold quality
ectocervix	UBERON:0012249	94.81	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.98	gold quality
uterine cervix	UBERON:0000002	93.80	gold quality
adipose tissue	UBERON:0001013	93.37	gold quality
vagina	UBERON:0000996	93.19	gold quality
omental fat pad	UBERON:0010414	92.73	gold quality
thoracic mammary gland	UBERON:0005200	90.69	gold quality
left uterine tube	UBERON:0001303	90.64	gold quality
left ovary	UBERON:0002119	90.43	gold quality
right ovary	UBERON:0002118	90.38	gold quality
body of uterus	UBERON:0009853	89.48	gold quality
myometrium	UBERON:0001296	89.28	gold quality
ovary	UBERON:0000992	89.12	gold quality
skin of abdomen	UBERON:0001416	88.99	gold quality
skin of leg	UBERON:0001511	88.81	gold quality
zone of skin	UBERON:0000014	88.70	gold quality
endometrium	UBERON:0001295	87.15	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.47	gold quality
prostate gland	UBERON:0002367	86.29	gold quality
mucosa of stomach	UBERON:0001199	85.35	gold quality
left coronary artery	UBERON:0001626	84.53	gold quality
ascending aorta	UBERON:0001496	82.79	gold quality
right coronary artery	UBERON:0001625	82.67	gold quality
thoracic aorta	UBERON:0001515	82.66	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.43	gold quality
lower esophagus	UBERON:0013473	82.35	gold quality
urinary bladder	UBERON:0001255	82.11	gold quality
descending thoracic aorta	UBERON:0002345	82.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	121.57
E-ANND-3	yes	17.38
E-MTAB-7249	no	66.98

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

35 targets.

Target	Regulation
AKR1C2	Activation
ATM	Activation
CD24
CD44	Activation
CD7	Unknown
CDH1	Unknown
CDH2	Repression
CDKN1A	Repression
CKM	Repression
CTPS1	Activation
DKK1	Unknown
ERBB3	Repression
F2R	Repression
FBLN5
FN1	Activation
FOS	Activation
GDF15	Activation
ICAM1	Activation
IL10	Unknown
ILK	Repression
ITGB1	Activation
MMP2	Activation
MMP9
MYB	Repression
NF1	Repression
NR2F1	Activation
PFDN4	Repression
POSTN	Unknown
RAP1A	Repression
RBL2	Repression

Upstream regulators (CollecTRI, top): HAND1, HIF1A, MEF2A, OVOL2, PITX2, STAT3, TWIST2

miRNA regulators (miRDB)

63 targeting TWIST2, 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-4673	100.00	66.64	1490
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-3140-5P	99.39	69.04	1136

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Epigenetic silencing of TWIST2 in mutated Ig V(H)is associated with chronic lymphocytic leukemia (PMID:15809452)
• findings suggest that reduced expression of TWIST suppresses the multistep process of peritoneal dissemination (detachment from the primary lesion, adhesion to MCs and invasion of MCs). (PMID:17487558)
• Twist proteins promote malignant conversion and metastatic dissemination. (PMID:18598946)
• hypoxic TWIST1 induction is regulated by both HIF-1 and HIF-2 proteins through distinct regulatory elements in a tissue-specific manner (PMID:19644484)
• increased expression in T-cell is associated with resistance to apoptosis and tumor progression (PMID:19937140)
• TWIST2 recessive mutations cause an focal facial dermal dysplasias and dominant TWIST1 mutations cause Saethre-Chotzen craniocynostosis suggests that they function independently in skin and bone development. (PMID:20691403)
• Our data implicate dermo1 as a tumor suppressor gene and a valuable molecular marker for human cancer (PMID:21109964)
• overexpression of HIF-1alpha, TWIST2 or SNIP1 correlated with poor disease-free survival in patients with tongue squamous cell carcinoma (PMID:21167768)
• overexpression of Twist2 may contribute to breast cancer progression by activating the epithelial to mesenchymal transition programme and enhancing the self-renewal of cancer stem-like cells. (PMID:21602879)
• Study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS. (PMID:21738662)
• these data suggest that the C-terminal domain of TWIST2, which is missing in the Q119X mutant form of TWIST2, is responsible for proper transactivation of the periostin gene. (PMID:21801849)
• Twist1 and Twist2 modulate ATF4-dependent transcriptional activity in response to Parathyroid hormone. (PMID:21866569)
• Mexican-Nahua sibs with facial and ophthalmologic features of FFDD type III were evaluated. Genomic DNAs were isolated for sequencing of the TWIST2 gene. The affected sibs were homozygous for a novel TWIST2 frameshift mutation, c.168delC (p.S57AfsX45). (PMID:21931173)
• TWIST2 overexpression was linked to cervix cancer progression, which makes it a promising marker for determining the metastatic potential. (PMID:22018873)
• This study suggests a dual role for epigenetic inactivation of TWIST2 in acute lymphoblastic leukemia, initially through altering cell growth and survival properties and subsequently by increasing resistance to chemotherapy. (PMID:22058208)
• Elevated expression of TWIST2 can contribute to invasion and metastasis of adenoid cystic carcinoma (ACC), and there might be some correlation between the hypoxia microenvironment and epithelial-mesenchymal transition in ACC. (PMID:22103974)
• upregulation of TWIST2, correlated with poor differentiation grade and shorter survival and identifies a subset of node-positive oral cavity/pharynx cancer patients with very poor prognosis (PMID:22201613)
• heterogeneous expression of Twist2 in breast tumors may have a functional link to tumor progression (PMID:23133563)
• Data indicate that the expression of Twist2 and Runx2 differs significantly in mesenchymal stromal cells from bone marrow (bmMSC) compared to MSC from term placenta (pMSC). (PMID:23763516)
• These data highlight a pivotal role for miR-138 in the regulation of colorectal cancer metastasis by targeting TWIST2. (PMID:24171926)
• identification of the Twist2-CD24 signaling pathway provides a potential therapeutic approach to target cancer stem cells in HCCs (PMID:24193512)
• nuclear beta-catenin is accumulated in Twist2-induced EMT cells to facilitates ovarian cancer invasion and metastasis. (PMID:24244294)
• Twist2 is the key Twist isoform coupling aberrant signals from pithelial-mesenchymal transition (EMT) to senescence and is an important candidate biomarker for cervical cancer prognosis. (PMID:24974259)
• LPS promotes PDCD4 degradation via a pathway involving PI3K and mTOR, releasing Twist2, which induces IL-10 via c-Maf. (PMID:24982420)
• Data have identified a novel TWIST2-p21 axis that regulates the cell cycle of both normal and leukemic hematopoietic cells, which implicates TWIST2 as a novel tumor suppressor in human acute myeloid leukemia. (PMID:25088197)
• A homozygous missense mutation in the TWIST2 gene was described in 3 siblings affected by Setleis syndrome. An alteration of bHLH domain, and loss of transcription factor’s function was predicted due to protein substitution. (PMID:25410422)
• Results show that Twist2 expression was gradually increased during the progression from normal cervical squamous epithelium to cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma. (PMID:25420506)
• Data suggest that TWIST1 and to a lesser degree TWIST2 expressed within the tumor stroma could contribute to the epithelial-mesenchymal transition (EMT)-like tumor budding phenotype in colorectal cancers. (PMID:25528769)
• Twist2 plays roles in osteogenesis differentiation, tumor formation and epithelial-mesenchymal transition.[review] (PMID:25608809)
• TWIST1 and TWIST2 are expressed in skeletal muscle and remained unaltered in metabolic diseases. (PMID:25663706)
• In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations (PMID:25728400)
• MACC1 promotes vasculogenic mimicry in gastric cancer by regulating the HGF/c-Met-TWIST1/2 signaling pathway. (PMID:25895023)
• After chronic NOD2 stimulation, Twist1 and Twist2 coordinate the regulation of both transcriptional activators and repressors, thereby mediating optimal cytokine down-regulation. (PMID:26019273)
• A substituted lysine at TWIST2 residue 75 results in Ablepharon Macrostomia Syndrome, whereas a glutamine or alanine yields Barber-Say Syndrome. (PMID:26119818)
• Findings indicated that HIF-2alpha promotes epithelial-mesenchymal transition in pancreatic cancer by regulating Twist2 binding to the promoter of E-cadherin. (PMID:26842802)
• TWIST2 regulates epithelial-mesenchymal transition by depriving the epithelial cell phenotype of E-cadherin and endowing the mesenchymal cell phenotype with Vimentin, which may be involved in the progression and prognosis of ovarian cancer. (PMID:27048119)
• epithelial membrane protein 3 is a downstream effector of TWIST1/2 in inducing epithelial-to-mesenchymal transition in gastric cancer. Epithelial membrane protein 3 upregulation might be associated with gastric cancer metastasis and is a potential indicator of unfavorable overall survival and progression-free survival in gastric cancer patients (PMID:28718375)
• Together, these data suggest that the S18-2 protein induces epithelial to mesenchymal cell transition through the TWIST2/E-cadherin signalling and, consequently, CXCR4-mediated migration of prostate cancer cells. (PMID:29396484)
• Twist1/2 can bind to the MMP2 promoter and promote its transcription, enhancing the invasive potential of colorectal cancer cells. (PMID:30556860)
• findings indicate that during differentiation, Twist2 globally shifts MyoD activity from myogenic loci to EMT and tumor growth loci through competition and epigenetic modifications at promoters and enhancers, highlighting the central role of TWIST2 in rhabdomyosarcoma pathogenesis (PMID:30975722)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	twist2	ENSDARG00000078266
mus_musculus	Twist2	ENSMUSG00000007805
rattus_norvegicus	Twist2	ENSRNOG00000020355
drosophila_melanogaster	twi	FBGN0003900
drosophila_melanogaster	HLH54F	FBGN0022740
drosophila_melanogaster	Hand	FBGN0032209
drosophila_melanogaster	Fer3	FBGN0037937
drosophila_melanogaster	CG33557	FBGN0053557
caenorhabditis_elegans		WBGENE00001953
caenorhabditis_elegans		WBGENE00001956

Paralogs (13): HAND1 (ENSG00000113196), TCF21 (ENSG00000118526), TWIST1 (ENSG00000122691), TCF15 (ENSG00000125878), FERD3L (ENSG00000146618), TCF23 (ENSG00000163792), HAND2 (ENSG00000164107), PTF1A (ENSG00000168267), MSC (ENSG00000178860), FIGLA (ENSG00000183733), BHLHA9 (ENSG00000205899), SCX (ENSG00000260428), TCF24 (ENSG00000261787)

Protein

Protein identifiers

Twist-related protein 2 — Q8WVJ9 (reviewed: Q8WVJ9)

Alternative names: Class A basic helix-loop-helix protein 39, Dermis-expressed protein 1

All UniProt accessions (1): Q8WVJ9

UniProt curated annotations — full annotation on UniProt →

Function. Binds to the E-box consensus sequence 5’-CANNTG-3’ as a heterodimer and inhibits transcriptional activation by MYOD1, MYOG, MEF2A and MEF2C. Also represses expression of pro-inflammatory cytokines such as TNFA and IL1B. Involved in postnatal glycogen storage and energy metabolism. Inhibits the premature or ectopic differentiation of preosteoblast cells during osteogenesis, possibly by changing the internal signal transduction response of osteoblasts to external growth factors.

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Forms a heterodimer with TCF3/E12. Also interacts with MEF2C.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. In the embryo, highly expressed in chondrogenic cells. In embryonic skin, expressed in the undifferentiated mesenchymal layer beneath the epidermis which later develops into the dermis. Expressed in early myeloid cells but not in lymphoid cells in the liver. Expression also detected in the secretory ependymal epithelium of the choroid plexus primordium. In the adult, expressed in secreting glandular tissues and tubules.

Disease relevance. Focal facial dermal dysplasia 3, Setleis type (FFDD3) [MIM:227260] A form of focal facial dermal dysplasia, a group of developmental defects characterized by bitemporal or preauricular skin lesions resembling aplasia cutis congenita. FFDD3 is characterized by distinctive bitemporal scar-like depressions resembling forceps marks, and additional facial features, including a coarse and leonine appearance, absent eyelashes on both lids or multiple rows on the upper lids, absent Meibomian glands, slanted eyebrows, chin clefting, and hypo- or hyperpigmentation of the skin. Histologically, the bitemporal lesion is an ectodermal dysplasia with near absence of subcutaneous fat, suggesting insufficient migration of neural crest cells into the frontonasal process and the first branchial arch. The disease is caused by variants affecting the gene represented in this entry. Ablepharon-macrostomia syndrome (AMS) [MIM:200110] A congenital ectodermal dysplasia characterized by absent eyelids, macrostomia, microtia, redundant skin, sparse hair, dysmorphic nose and ears, variable abnormalities of the nipples, genitalia, fingers, and hands, largely normal intellectual and motor development, and poor growth. The disease is caused by variants affecting the gene represented in this entry. Barber-Say syndrome (BBRSAY) [MIM:209885] A rare ectodermal dysplasia characterized by ectropion, macrostomia, ear abnormalities, broad nasal bridge, bulbous nose, redundant skin, hypertrichosis, dental abnormalities, and variable other features. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001258822, NP_476527 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR047094	Twist2_bHLH	Domain
IPR050283	E-box_TF_Regulators	Family

Pfam: PF00010

UniProt features (11 total): sequence variant 5, sequence conflict 2, chain 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WVJ9-F1	73.94	0.46

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-8878166	Transcriptional regulation by RUNX2
R-HSA-9764725	Negative Regulation of CDH1 Gene Transcription

MSigDB gene sets: 369 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, HNF3ALPHA_Q6, GOBP_OSTEOBLAST_DIFFERENTIATION, CHANDRAN_METASTASIS_DN, CLASPER_LYMPHATIC_VESSELS_DURING_METASTASIS_DN, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, MODULE_205, WONG_ENDMETRIUM_CANCER_DN, INGRAM_SHH_TARGETS_UP, FOXJ2_01, HFH3_01, GOBP_OSSIFICATION, GOBP_REGULATION_OF_OSTEOBLAST_DIFFERENTIATION, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS

GO Biological Process (6): regulation of transcription by RNA polymerase II (GO:0006357), cell differentiation (GO:0030154), positive regulation of cell migration (GO:0030335), developmental process (GO:0032502), negative regulation of osteoblast differentiation (GO:0045668), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (5): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), protein dimerization activity (GO:0046983), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Generic Transcription Pathway	1
Regulation of CDH1 Gene Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	2
nuclear lumen	2
cellular anatomical structure	2
transcription by RNA polymerase II	1
cellular developmental process	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
biological_process	1
osteoblast differentiation	1
negative regulation of cell differentiation	1
regulation of osteoblast differentiation	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transcription cis-regulatory region binding	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
protein binding	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TWIST2	SNAI1	O95863	840
TWIST2	RUNX2	Q13950	826
TWIST2	SNAI2	O43623	790
TWIST2	ZEB1	P37275	748
TWIST2	ZEB2	O60315	748
TWIST2	CDH1	P12830	680
TWIST2	MSX2	P35548	628
TWIST2	TCF3	P15883	624
TWIST2	CDH2	P19022	619
TWIST2	BGLAP	P02818	587
TWIST2	FOXC2	Q99958	578
TWIST2	VIM	P08670	576
TWIST2	SNAI3	Q3KNW1	559
TWIST2	FGFR2	P18443	550
TWIST2	POSTN	Q15063	547

IntAct

75 interactions, top by confidence:

A	B	Type	Score
TWIST2	TCF4	psi-mi:“MI:0915”(physical association)	0.740
TCF4	TWIST2	psi-mi:“MI:0915”(physical association)	0.740
TCF12	TWIST2	psi-mi:“MI:0915”(physical association)	0.670
TWIST2	TCF12	psi-mi:“MI:0915”(physical association)	0.670
CCM2	TWIST2	psi-mi:“MI:0915”(physical association)	0.570
TWIST2	CCM2	psi-mi:“MI:0915”(physical association)	0.570
TCF3	TWIST2	psi-mi:“MI:0915”(physical association)	0.560
TWIST2	TCF12	psi-mi:“MI:0915”(physical association)	0.560
	TWIST2	psi-mi:“MI:0915”(physical association)	0.560
TWIST2	GLIS2	psi-mi:“MI:0915”(physical association)	0.560
TWIST2	A2M	psi-mi:“MI:0915”(physical association)	0.560
TWIST2	DCTN1	psi-mi:“MI:0915”(physical association)	0.560
TWIST2		psi-mi:“MI:0915”(physical association)	0.560
TWIST2	PMP22	psi-mi:“MI:0915”(physical association)	0.560
TWIST2	ATXN10	psi-mi:“MI:0915”(physical association)	0.560
SNCA	TWIST2	psi-mi:“MI:0915”(physical association)	0.560
HTT	TWIST2	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	TWIST2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (27): TWIST2 (Two-hybrid), TWIST2 (Two-hybrid), TWIST2 (Two-hybrid), TWIST2 (Two-hybrid), TWIST2 (Two-hybrid), CCM2 (Affinity Capture-Luminescence), TCF12 (Two-hybrid), TWIST2 (Affinity Capture-MS), TWIST2 (Two-hybrid), TWIST2 (Reconstituted Complex), TWIST2 (Two-hybrid), TWIST2 (Two-hybrid), TWIST2 (Two-hybrid), TWIST2 (Two-hybrid), MEF2C (Affinity Capture-Western)

ESM2 similar proteins: A1L2X1, D4A7E1, E1BD44, F1QW76, F7EMX9, G5ECU7, G5EF76, O09015, O35284, O57598, O96642, P13096, P13097, P13098, P13903, P46505, P50539, P50540, P50541, P97831, P97876, Q00P32, Q01068, Q01069, Q01070, Q01071, Q04788, Q05195, Q07291, Q09771, Q09926, Q0VFI9, Q0VH34, Q10574, Q16520, Q18711, Q21361, Q23579, Q62282, Q8AW52

Diamond homologs: A8E5T6, B6VQA1, O13125, O13126, O16867, O35437, O42202, O42606, O43680, O57598, O60682, O73615, O73823, O88940, O93507, O96004, O96642, P13903, P17542, P22091, P24899, P26687, P46581, P48985, P48987, P57100, P57101, P57102, P59101, P61295, P61296, P70661, P79765, P79782, P97831, P97832, Q02575, Q02576, Q02577, Q0VCE2

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
TWIST2	“down-regulates quantity by repression”	MYB	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	GDF15	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	SRPX	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	AKR1C2	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	ATM	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	CTPS1	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	ERBB3	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	F2R	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	FOS	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	ILK	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	NF1	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	NR2F1	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	PFDN4	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	RAP1A	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	RBL2	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	ITGB1	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	ICAM1	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	CD44	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	CDH1	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	RUNX2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 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
nervous system development	5	13.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	0
Uncertain significance	24
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
208076	NM_001271893.4(TWIST2):c.224A>C (p.Glu75Ala)	Pathogenic
208077	NM_001271893.4(TWIST2):c.223G>A (p.Glu75Lys)	Pathogenic
208078	NM_001271893.4(TWIST2):c.223G>C (p.Glu75Gln)	Pathogenic
208079	NM_001271893.4(TWIST2):c.229_234dup (p.Gln77_Arg78dup)	Pathogenic
30678	NM_001271893.4(TWIST2):c.355C>T (p.Gln119Ter)	Pathogenic
30679	NM_001271893.4(TWIST2):c.193C>T (p.Gln65Ter)	Pathogenic
39840	NM_001271893.4(TWIST2):c.168del (p.Ser57fs)	Pathogenic

SpliceAI

1297 predictions. Top by Δscore:

Variant	Effect	Δscore
2:238848732:GG:G	donor_gain	1.0000
2:238848733:GG:G	donor_gain	1.0000
2:238848732:GGGTA:G	donor_loss	0.9900
2:238850036:ATGT:A	acceptor_gain	0.9900
2:238850037:T:G	acceptor_gain	0.9900
2:238848734:G:GG	donor_gain	0.9800
2:238850039:T:TA	acceptor_gain	0.9800
2:238877895:G:T	donor_gain	0.9800
2:238878126:G:GT	donor_gain	0.9700
2:238886778:G:C	acceptor_gain	0.9700
2:238886775:CCAG:C	acceptor_gain	0.9600
2:238886777:A:AG	acceptor_gain	0.9600
2:238886778:G:GG	acceptor_gain	0.9600
2:238848641:C:G	donor_gain	0.9500
2:238848734:G:T	donor_gain	0.9500
2:238864161:G:GG	donor_gain	0.9500
2:238886778:GA:G	acceptor_gain	0.9500
2:238877862:GAAAA:G	donor_gain	0.9400
2:238864067:ACCCT:A	acceptor_gain	0.9300
2:238877867:G:GG	donor_gain	0.9300
2:238886778:GAGGA:G	acceptor_gain	0.9300
2:238848617:C:G	donor_gain	0.9200
2:238877866:A:AG	donor_gain	0.9000
2:238878077:G:GT	donor_gain	0.9000
2:238886776:CAG:C	acceptor_gain	0.9000
2:238886777:AGA:A	acceptor_gain	0.9000
2:238863118:GCCC:G	donor_gain	0.8900
2:238886746:A:AG	acceptor_gain	0.8900
2:238886747:G:GG	acceptor_gain	0.8900
2:238875498:AAGG:A	donor_gain	0.8800

AlphaMissense

1058 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:238848417:C:A	R68S	1.000
2:238848427:C:A	A71D	1.000
2:238848431:C:A	N72K	1.000
2:238848431:C:G	N72K	1.000
2:238848435:C:A	R74S	1.000
2:238848436:G:C	R74P	1.000
2:238848438:G:A	E75K	1.000
2:238848439:A:C	E75A	1.000
2:238848439:A:T	E75V	1.000
2:238848440:G:C	E75D	1.000
2:238848440:G:T	E75D	1.000
2:238848441:C:A	R76S	1.000
2:238848441:C:T	R76C	1.000
2:238848442:G:C	R76P	1.000
2:238848447:C:A	R78S	1.000
2:238848447:C:G	R78G	1.000
2:238848447:C:T	R78C	1.000
2:238848448:G:C	R78P	1.000
2:238848456:T:C	S81P	1.000
2:238848460:T:A	L82H	1.000
2:238848460:T:C	L82P	1.000
2:238848464:C:A	N83K	1.000
2:238848464:C:G	N83K	1.000
2:238848468:G:C	A85P	1.000
2:238848471:T:C	F86L	1.000
2:238848472:T:C	F86S	1.000
2:238848472:T:G	F86C	1.000
2:238848473:C:A	F86L	1.000
2:238848473:C:G	F86L	1.000
2:238848481:T:A	L89Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000080500 (2:238880759 A>C,G,T), RS1000183923 (2:238861105 G>A,T), RS1000263919 (2:238901208 C>T), RS1000318124 (2:238852107 C>T), RS1000326326 (2:238888261 G>A), RS1000382771 (2:238861285 A>G,T), RS1000421235 (2:238857263 T>A), RS1000483114 (2:238910490 T>C,G), RS1000542493 (2:238899840 C>T), RS1000572742 (2:238895552 G>A), RS1000586930 (2:238910799 G>A), RS1000611586 (2:238896311 G>A,T), RS1000624675 (2:238857458 T>C), RS1000653180 (2:238853386 A>G), RS1000684834 (2:238864152 G>A)

Disease associations

OMIM: gene MIM:607556 | disease phenotypes: MIM:209885, MIM:200110, MIM:227260

GenCC curated gene-disease

Disease	Classification	Inheritance
ablepharon macrostomia syndrome	Definitive	Autosomal dominant
Barber-Say syndrome	Strong	Autosomal dominant
focal facial dermal dysplasia type III	Strong	Autosomal recessive

Mondo (3): Barber-Say syndrome (MONDO:0008853), ablepharon macrostomia syndrome (MONDO:0008693), focal facial dermal dysplasia type III (MONDO:0009203)

Orphanet (4): Barber-Say syndrome (Orphanet:1231), Ablepharon macrostomia syndrome (Orphanet:920), Focal facial dermal dysplasia type III (Orphanet:1807), Focal facial dermal dysplasia (Orphanet:398166)

HPO phenotypes

130 total (30 of 130 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000049	Shawl scrotum
HP:0000054	Micropenis
HP:0000055	Abnormal female external genitalia morphology
HP:0000059	Hypoplastic labia majora
HP:0000062	Ambiguous genitalia
HP:0000064	Hypoplastic labia minora
HP:0000154	Wide mouth
HP:0000188	Short upper lip
HP:0000212	Gingival overgrowth
HP:0000215	Thick upper lip vermilion
HP:0000218	High palate
HP:0000220	Velopharyngeal insufficiency
HP:0000233	Thin vermilion border
HP:0000271	Abnormality of the face
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000402	Stenosis of the external auditory canal
HP:0000413	Atresia of the external auditory canal
HP:0000414	Bulbous nose

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST003983_3	Male-pattern baldness	2.000000e-37
GCST005116_19	Male-pattern baldness	1.000000e-39
GCST005790_88	Rosacea symptom severity	1.000000e-06
GCST006661_273	Male-pattern baldness	1.000000e-40
GCST006661_38	Male-pattern baldness	7.000000e-12
GCST006988_129	Blond vs. brown/black hair color	3.000000e-12
GCST007565_124	Morning person	8.000000e-36
GCST007565_209	Morning person	3.000000e-18
GCST007692_12	Chronic obstructive pulmonary disease	3.000000e-07
GCST007692_95	Chronic obstructive pulmonary disease	3.000000e-12
GCST011011_20	Youthful appearance (self-reported)	3.000000e-13
GCST90016669_3	Pancreas volume	2.000000e-08
GCST90020025_1755	Waist-to-hip ratio adjusted for BMI	4.000000e-09
GCST90020027_596	Waist-hip index	3.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009180	rosacea severity measurement
EFO:0003924	hair color
EFO:0008328	chronotype measurement
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C535557	Ablepharon macrostomia syndrome (supp.)
C537908	Barber Say syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	affects cotreatment, increases methylation, increases expression	2
bisphenol A	decreases methylation, affects cotreatment, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
napabucasin	decreases expression	1
arsenite	increases expression, affects reaction	1
sodium arsenite	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1
aflatoxin B2	decreases methylation	1
evodiamine	increases expression	1
arsenic trichloride	affects binding, decreases reaction	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	increases reaction, affects binding	1
3-nitrobenzanthrone	increases expression, affects reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
GSK-2816126	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzene	decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cisplatin	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Dietary Carbohydrates	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7Q9	SEES3-1V human TWIST2, clone1	Embryonic stem cell	Male
CVCL_A7R0	SEES3-1V human TWIST2, clone2	Embryonic stem cell	Male
CVCL_A7R1	SEES3-1V human TWIST2, clone3	Embryonic stem cell	Male
CVCL_B8A6	Abcam Raji TWIST2 KO	Cancer cell line	Male
CVCL_C0B0	Abcam THP-1 TWIST2 KO	Cancer cell line	Male
CVCL_C7CN	Abcam PC-3 TWIST2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310642	PHASE4	COMPLETED	Efficacy of Prophylactic Treatment of Oral Prochlorperazine for Acute Mountain Sickness
NCT01923376	Not specified	WITHDRAWN	Hepatic Encephalopathy: Lactulose or Polyethylene Glycol (H.E.L.P.)