WTAP

Summary

WTAP (WT1 associated protein, HGNC:16846) is a protein-coding gene on chromosome 6q25.3, encoding Pre-mRNA-splicing regulator WTAP (Q15007). Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing. It is a selective cancer dependency (DepMap: 66.6% of cell lines).

The Wilms tumor suppressor gene WT1 appears to play a role in both transcriptional and posttranscriptional regulation of certain cellular genes. This gene encodes a WT1-associating protein, which is a ubiquitously expressed nuclear protein. Like WT1 protein, this protein is localized throughout the nucleoplasm as well as in speckles and partially colocalizes with splicing factors. Alternative splicing of this gene results in several transcript variants encoding three different isoforms.

Source: NCBI Gene 9589 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• GTEx eGene: eQTL in 38 tissues, sQTL in 17 (q < 0.05)
• Cancer dependency (DepMap): dependent in 66.6% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.34 (highly constrained)
• MANE Select transcript: NM_001270531
• Interaction hub: 1,767 STRING partners (top 10% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16846
Approved symbol	WTAP
Name	WT1 associated protein
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0105, MGC3925, Mum2
Ensembl gene	ENSG00000146457
Ensembl biotype	protein_coding
OMIM	605442
Entrez	9589

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 14 protein_coding, 5 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000621533

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 1, TSL 5: 1

ENST00000621533, ENST00000337387, ENST00000358372, ENST00000462110, ENST00000494513, ENST00000614346, ENST00000631126, ENST00000650096, ENST00000971718, ENST00000971719, ENST00000971720, ENST00000971721, ENST00001053299, ENST00001078263, ENST00001078264, ENST00001078265, ENST00001078266, ENST00001078267, ENST00001094607, ENST00001094608, ENST00001137735

RefSeq mRNA: 6 — MANE Select: NM_001270531 NM_001270531, NM_001270532, NM_001270533, NM_004906, NM_152857, NM_152858

CCDS: CCDS5266, CCDS5267, CCDS75542

Canonical transcript exons

ENST00000621533 — 8 exons

Exon	Start	End
ENSE00001273785	159753460	159753614
ENSE00003748790	159727506	159727703
ENSE00003888888	159738990	159739045
ENSE00003888972	159736258	159736295
ENSE00003889132	159742088	159742146
ENSE00003889383	159748191	159748369
ENSE00003889497	159743665	159743792
ENSE00003893598	159755028	159756319

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 123.1876 / max 1044.9606, expressed in 1828 samples.

Highest expression (Bgee): secondary oocyte, oocyte, epithelium of nasopharynx, vena cava, buccal mucosa cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

WTAP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 17 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 55 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	2.6e-42	+1.25	6:159741407:A:G
Testis	eqtl	5.4e-32	+0.84	6:159741407:A:G
Spleen	eqtl	1.4e-29	+1.78	6:159741407:A:G
Nerve Tibial	eqtl	1.5e-24	+0.78	6:159741407:A:G
Testis	sqtl	5.9e-24	-2.24	6:159741407:A:G
Pancreas	eqtl	1.8e-21	+1.09	6:159741407:A:G
Skin Sun Exposed Lower leg	eqtl	6.6e-18	+0.71	6:159741407:A:G
Esophagus Mucosa	eqtl	3.0e-16	+0.92	6:159741407:A:G
Skin Not Sun Exposed Suprapubic	eqtl	4.6e-16	+0.66	6:159741407:A:G
Adipose Visceral Omentum	eqtl	6.9e-16	+0.23	6:159750846:C:CCT
Adipose Subcutaneous	eqtl	2.5e-15	+0.23	6:159747888:T:TTAAA
Esophagus Muscularis	eqtl	5.1e-14	+0.56	6:159665056:G:A
Thyroid	sqtl	1.5e-12	-1.47	6:159761764:G:C
Colon Transverse	eqtl	6.1e-12	+0.82	6:159665056:G:A
Artery Tibial	eqtl	9.2e-12	+0.20	6:159762293:G:C
Breast Mammary Tissue	eqtl	3.1e-11	+0.60	6:159741407:A:G
Stomach	eqtl	6.5e-11	+0.90	6:159665056:G:A
Whole Blood	eqtl	3.3e-10	+0.41	6:159665056:G:A
Liver	eqtl	9.8e-10	+0.95	6:159665056:G:A
Lung	eqtl	2.6e-09	+0.57	6:159665056:G:A

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
70972	55.7005	1824
70970	38.1788	1825
70973	24.5009	1727
70971	3.4414	1480
204275	0.5778	349
70969	0.2701	109
70974	0.2632	123
70975	0.2549	89

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.76	gold quality
oocyte	CL:0000023	99.43	gold quality
epithelium of nasopharynx	UBERON:0001951	99.09	gold quality
vena cava	UBERON:0004087	98.89	gold quality
buccal mucosa cell	CL:0002336	98.77	gold quality
cartilage tissue	UBERON:0002418	98.74	gold quality
amniotic fluid	UBERON:0000173	98.08	gold quality
germinal epithelium of ovary	UBERON:0001304	98.07	gold quality
pericardium	UBERON:0002407	98.03	gold quality
parietal pleura	UBERON:0002400	97.87	gold quality
caput epididymis	UBERON:0004358	97.73	gold quality
ganglionic eminence	UBERON:0004023	97.70	gold quality
bone marrow	UBERON:0002371	97.50	gold quality
palpebral conjunctiva	UBERON:0001812	97.49	gold quality
esophagus squamous epithelium	UBERON:0006920	97.49	gold quality
pharyngeal mucosa	UBERON:0000355	97.48	gold quality
thymus	UBERON:0002370	97.46	gold quality
corpus epididymis	UBERON:0004359	97.40	gold quality
cauda epididymis	UBERON:0004360	97.39	gold quality
endometrium	UBERON:0001295	97.34	gold quality
tonsil	UBERON:0002372	97.33	gold quality
lymph node	UBERON:0000029	97.27	gold quality
ventricular zone	UBERON:0003053	97.27	gold quality
pleura	UBERON:0000977	97.22	gold quality
gingival epithelium	UBERON:0001949	97.21	gold quality
saphenous vein	UBERON:0007318	97.11	gold quality
gastrocnemius	UBERON:0001388	97.07	gold quality
tibia	UBERON:0000979	97.05	gold quality
embryo	UBERON:0000922	96.85	gold quality
visceral pleura	UBERON:0002401	96.84	gold quality
granulocyte	CL:0000094	96.83	gold quality
gingiva	UBERON:0001828	96.82	gold quality
superior surface of tongue	UBERON:0007371	96.82	gold quality
trachea	UBERON:0003126	96.75	gold quality
cortical plate	UBERON:0005343	96.73	gold quality
cerebellar vermis	UBERON:0004720	96.71	gold quality
left uterine tube	UBERON:0001303	96.67	gold quality
trabecular bone tissue	UBERON:0002483	96.67	gold quality
ovary	UBERON:0000992	96.63	gold quality
rectum	UBERON:0001052	96.62	gold quality
smooth muscle tissue	UBERON:0001135	96.62	gold quality
renal glomerulus	UBERON:0000074	96.58	gold quality
epithelium of esophagus	UBERON:0001976	96.58	gold quality
body of tongue	UBERON:0011876	96.58	gold quality
tongue	UBERON:0001723	96.56	gold quality
muscle of leg	UBERON:0001383	96.55	gold quality
uterus	UBERON:0000995	96.53	gold quality
decidua	UBERON:0002450	96.53	gold quality
middle temporal gyrus	UBERON:0002771	96.53	gold quality
peritoneum	UBERON:0002358	96.52	gold quality
omental fat pad	UBERON:0010414	96.51	gold quality
adipose tissue of abdominal region	UBERON:0007808	96.50	gold quality
female reproductive system	UBERON:0000474	96.49	gold quality
leukocyte	CL:0000738	96.47	gold quality
metanephric glomerulus	UBERON:0004736	96.45	gold quality
thoracic mammary gland	UBERON:0005200	96.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.43	gold quality
mammary gland	UBERON:0001911	96.42	gold quality
urethra	UBERON:0000057	96.40	gold quality
monocyte	CL:0000576	96.39	gold quality
mononuclear cell	CL:0000842	96.39	gold quality
penis	UBERON:0000989	96.36	gold quality
prostate gland	UBERON:0002367	96.34	gold quality
ectocervix	UBERON:0012249	96.34	gold quality
skin of abdomen	UBERON:0001416	96.29	gold quality
mammary duct	UBERON:0001765	96.28	gold quality
calcaneal tendon	UBERON:0003701	96.28	gold quality
adrenal tissue	UBERON:0018303	96.28	gold quality
left ovary	UBERON:0002119	96.26	gold quality
islet of Langerhans	UBERON:0000006	96.24	gold quality
vagina	UBERON:0000996	96.24	gold quality
mucosa of stomach	UBERON:0001199	96.21	gold quality
adipose tissue	UBERON:0001013	96.20	gold quality
connective tissue	UBERON:0002384	96.20	gold quality
endocervix	UBERON:0000458	96.18	gold quality
oral cavity	UBERON:0000167	96.17	gold quality
bone marrow cell	CL:0002092	96.16	gold quality
placenta	UBERON:0001987	96.13	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.13	gold quality
caecum	UBERON:0001153	96.12	gold quality
gall bladder	UBERON:0002110	96.11	gold quality
epithelium of mammary gland	UBERON:0003244	96.10	gold quality
jejunum	UBERON:0002115	96.09	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.08	gold quality
body of uterus	UBERON:0009853	96.08	gold quality
squamous epithelium	UBERON:0006914	96.07	gold quality
body of pancreas	UBERON:0001150	96.03	gold quality
fallopian tube	UBERON:0003889	96.03	gold quality
pancreas	UBERON:0001264	96.01	gold quality
trigeminal ganglion	UBERON:0001675	96.01	gold quality
zone of skin	UBERON:0000014	96.00	gold quality
synovial joint	UBERON:0002217	95.98	gold quality
skin of leg	UBERON:0001511	95.95	gold quality
skin of hip	UBERON:0001554	95.94	gold quality
muscle organ	UBERON:0001630	95.93	gold quality
myometrium	UBERON:0001296	95.92	gold quality
right ovary	UBERON:0002118	95.91	gold quality
parotid gland	UBERON:0001831	95.88	gold quality
minor salivary gland	UBERON:0001830	95.87	gold quality
mouth mucosa	UBERON:0003729	95.87	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10137	no	5991.92
E-GEOD-76312	no	2283.28
E-GEOD-124858	no	1705.01
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	231.3	high
Urinary bladder	tissue	95.6	high
Thymus	tissue	83.6
Tonsil	tissue	75.6	high
Lymph node	tissue	72.4	high
Spinal cord	tissue	67.0
Pons	tissue	65.9
Corpus callosum	tissue	65.3
Breast	tissue	64.7	high
Midbrain	tissue	64.4
Superior colliculi	tissue	63.6
Tongue	tissue	63.0
Hypothalamus	tissue	62.9
Thalamus	tissue	61.7
Epididymis	tissue	61.5	high
Medulla oblongata	tissue	61.5
Cerebellum	tissue	61.5	high
Substantia nigra	tissue	61.1
Septum	tissue	60.4
Ovary	tissue	60.0	medium
Hippocampal formation	tissue	59.8
Putamen	tissue	59.0
Appendix	tissue	58.7	high
Placenta	tissue	58.0	high
Vagina	tissue	56.3	medium
Adipose tissue	tissue	55.0	medium
Ventral forebrain	tissue	54.6
Periaqueductal gray	tissue	54.6
Prostate	tissue	52.7	medium
Endometrium 1	tissue	52.6	medium
Cerebral cortex	tissue	52.3	high
Occipital cortex	tissue	52.3
Motor cortex	tissue	52.0
Rectum	tissue	51.9	high
Olfactory bulb	tissue	51.9
Prefrontal cortex	tissue	51.8
Somatosensory cortex	tissue	51.7
Entorhinal cortex	tissue	51.1
Basal ganglia	tissue	50.7	medium
Retrosplenial and cingulate cortex	tissue	50.7
Skeletal muscle	tissue	50.3	low
Choroid plexus	tissue	50.2
Parathyroid gland	tissue	50.0	high
Gallbladder	tissue	48.9	high
Amygdala	tissue	48.5
Smooth muscle	tissue	48.1	medium
Retrosplenial cortex	tissue	47.9
Adrenal gland	tissue	47.7	high
Cervix	tissue	47.5	medium
Temporal cortex	tissue	47.5
Liver	tissue	47.4	low
Colon	tissue	47.3	high
Spleen	tissue	47.0	low
Insular cortex	tissue	46.5
Frontal cortex	tissue	46.3
Thyroid gland	tissue	46.1	high
Caudate putamen	tissue	46.1
Pituitary gland	tissue	45.1
Esophagus	tissue	45.1	high
Lung	tissue	45.0	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (67.0), Dorsal spinal cord (66.0), White matter (65.3), Dorsal hippocampus (59.8), Blood vessel (59.7).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3, WT1

miRNA regulators (miRDB)

Targeting WTAP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 121 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-124-3P	99.89	73.74	3043

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.343, missense Z 2.94 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000621533 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
6:159,736,266–159,755,166	120 / 287.6	0.42	no
6:159,755,167–159,755,608	175 / 183.1	0.96	no
DepMap (CRISPR cell-line fitness): dependent in 66.6% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): KP-3 (-1.707), G-292, clone A141B1 (-1.585), HPAF-II (-1.498), EFO-21 (-1.437), Panc 08.13 (-1.43), SK-N-AS (-1.4), NCI-H2887 (-1.374), RCM-1 (-1.357), JHOS-4 (-1.321), HCC38 (-1.27), Panc 03.27 (-1.267), NCI-N87 (-1.195), TEN (-1.184), Hs 852.T (-1.183), KP-N-YN (-1.181).

Literature-anchored findings (GeneRIF, showing 40)

• WTAP protein involved in the morphogenesis of the genitourinaty tract and in the etiology of isolated hypospadias. (PMID:14675924)
• WTAP and ATF3 Transcription Factor are activated in Wilms’ tumor and accelerate tumorigenesis. (PMID:16912181)
• WTAP as an essential factor for the stabilization of cyclin A2 mRNA, thereby regulating G2/M cell-cycle transition (PMID:17088532)
• WTAP is a novel regulator of the cell cycle and cell survival and implicate a WTAP-WT1 axis as a novel pathway for controlling vascular smooth muscle cell phenotype. (PMID:17095724)
• Nuclear degradation of Wilms tumor 1-associating protein and survivin splice variant switching underlie IGF-1-mediated survival (PMID:19605357)
• WTAP level in poodocytes is a valuable alternative technique in the study of podocyte injury in diabetic nephropathy. (PMID:19969384)
• WTAP overexpression made cancer cells more tumorigenic (PMID:22957919)
• WTAP regulates migration and invasion of cholangiocarcinoma cells. (PMID:23354623)
• the WTAP complex is a novel component of the RNA processing machinery, implying an important role in both posttranscriptional control and cell cycle regulation. (PMID:24100041)
• WTAP as a regulatory subunit is required for formation of a functional m6A methyltransferase complex including METTL3 and METTL14, which play an important role in the regulation of gene expression and alternative splicing. (PMID:24407421)
• WTAP has an important role in abnormal proliferation and arrested differentiation of leukemia cells, and WTAP is a novel client protein of Hsp90 (PMID:24413322)
• WTAP was over-expressed in glioma tissues, and the expression was closely correlated with glioma grade. (PMID:27370540)
• These findings suggest that WTAP may have an oncogenic role in RCC through physically binding to CDK2 transcript and enhancing its transcript stability which might provide new insights into RCC therapy. (PMID:29482572)
• WTAP is a client protein of Hsp90 and can appear in a complex with BCL6 and Hsp90 in DLBCL (PMID:30143009)
• Our study is the first to report that WTAP-mediated m6A methylation has a crucial role in HCC oncogenesis, and highlights WTAP as a potential therapeutic target of HCC treatment. (PMID:31438961)
• High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour-associated T lymphocyte infiltration. (PMID:32176425)
• Wilms’ tumour 1-associating protein inhibits endothelial cell angiogenesis by m6A-dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation. (PMID:32281240)
• WTAP and BIRC3 are involved in the posttranscriptional mechanisms that impact on the expression and activity of the human lactonase PON2. (PMID:32382056)
• WTAP gene single nucleotide polymorphism is associated with Wilms tumor susceptibility. (PMID:32504654)
• LncRNA PCGEM1 accelerates non-small cell lung cancer progression via sponging miR-433-3p to upregulate WTAP. (PMID:32787827)
• WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m(6)A-dependent manner. (PMID:32814762)
• Wilms’ tumor 1-associating protein contributes to psoriasis by promoting keratinocytes proliferation via regulating cyclinA2 and CDK2. (PMID:32866786)
• High Wilms’ tumor 1 associating protein expression predicts poor prognosis in acute myeloid leukemia and regulates m(6)A methylation of MYC mRNA. (PMID:32880751)
• Gene Signatures and Prognostic Values of m6A RNA Methylation Regulators in Ovarian Cancer. (PMID:32951457)
• Identification of WTAP-related genes by weighted gene co-expression network analysis in ovarian cancer. (PMID:32998774)
• m6A methyltransferase Wilms’ tumor 1-associated protein facilitates cell proliferation and cisplatin resistance in NK/T cell lymphoma by regulating dual-specificity phosphatases 6 expression via m6A RNA methylation. (PMID:33205540)
• ARRB2 promotes colorectal cancer growth through triggering WTAP. (PMID:33367479)
• N(6)-methyladenosine (m(6)A) methyltransferase WTAP accelerates the Warburg effect of gastric cancer through regulating HK2 stability. (PMID:33378974)
• WTAP facilitates progression of endometrial cancer via CAV-1/NF-kappaB axis. (PMID:33559954)
• Long Noncoding RNA DUXAP8 Promotes Pancreatic Carcinoma Cell Migration and Invasion Via Pathway by miR-448/WTAP/Fak Signaling Axis. (PMID:33625109)
• WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m(6)A modification of ATF4 mRNA. (PMID:33819187)
• C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1. (PMID:34312368)
• EBV downregulates the m(6)A ““writer”” WTAP in EBV-associated gastric carcinoma. (PMID:34329695)
• [The Relationship between HIF1alpha and WTAP Expression Level in t(8;21) Acute Myeloid Leukemia]. (PMID:34627420)
• LINC00839/miR-144-3p/WTAP (WT1 Associated protein) axis is involved in regulating hepatocellular carcinoma progression. (PMID:34634995)
• m(6)A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK. (PMID:34828353)
• N(6)-methyladenosine (m(6)A)-mediated lncRNA DLGAP1-AS1enhances breast canceradriamycin resistance through miR-299-3p/WTAP feedback loop. (PMID:34866525)
• WTAP-mediated m(6)A modification of lncRNA DIAPH1-AS1 enhances its stability to facilitate nasopharyngeal carcinoma growth and metastasis. (PMID:34999731)
• Upregulated WTAP expression in colorectal cancer correlates with tumor site and differentiation. (PMID:35143566)
• WTAP-mediated m(6)A modification of lncRNA NORAD promotes intervertebral disc degeneration. (PMID:35304463)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wtap	ENSDARG00000042642
mus_musculus	Wtap	ENSMUSG00000060475
rattus_norvegicus	Wtap	ENSRNOG00000019091
drosophila_melanogaster	fl(2)d	FBGN0000662

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1926395) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal embryo development	1
embryonic lethality, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Xenopus laevis	Q4KLT6	96.4%	Diamond
Xenopus tropicalis	Q6P4K5	96.4%	Diamond
Drosophila pseudoobscura pseudoobscura	Q28XY0	65.1%	Diamond
Arabidopsis thaliana	Q9ZSZ8	38.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ACAT2	protein-coding	39
SOD2	protein-coding	6648
SNORA20	snoRNA	677806
SNORA29	snoRNA	677812
TCP1	protein-coding	6950
SOD2-OT1	ncRNA	100129518
MRPL18	protein-coding	29074
PNLDC1	protein-coding	154197

Protein

Protein identifiers

Pre-mRNA-splicing regulator WTAP — Q15007 (reviewed: Q15007)

Alternative names: Female-lethal(2)D homolog, WT1-associated protein, Wilms tumor 1-associating protein

All UniProt accessions (2): A0A087X1R4, Q15007

UniProt curated annotations — full annotation on UniProt →

Function. Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing. Required for accumulation of METTL3 and METTL14 to nuclear speckle. Acts as a mRNA splicing regulator. Regulates G2/M cell-cycle transition by binding to the 3’ UTR of CCNA2, which enhances its stability. Impairs WT1 DNA-binding ability and inhibits expression of WT1 target genes.

Subunit / interactions. Component of the WMM complex, a N6-methyltransferase complex composed of a catalytic subcomplex, named MAC, and of an associated subcomplex, named MACOM. The MAC subcomplex is composed of METTL3 and METTL14. The MACOM subcomplex is composed of WTAP, ZC3H13, CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B). Interacts with WT1. Also a component of a MACOM-like complex, named WTAP complex, composed of WTAP, ZC3H13, CBLL1, VIRMA, RBM15, BCLAF1 and THRAP3.

Subcellular location. Nucleus speckle. Nucleus. Nucleoplasm. Cytoplasm.

Tissue specificity. Ubiquitously expressed.

Induction. In smooth muscle cells, up-regulated after serum withdrawal, when cells become mature and non proliferative.

Similarity. Belongs to the fl(2)d family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15007-1	1	yes
Q15007-2	2

RefSeq proteins (6): NP_001257460, NP_001257461, NP_001257462, NP_004897, NP_690596, NP_690597 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033757	WTAP	Family

Pfam: PF17098

UniProt features (23 total): modified residue 7, compositionally biased region 6, helix 4, splice variant 2, chain 1, region of interest 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
9XOE	Crystal structure of WTAP 1-50	X-RAY DIFFRACTION	1.65
7YFJ	Crystal structure of human WTAP	X-RAY DIFFRACTION	2.4
9XOF	Crystal structure of WTAP 150-245	X-RAY DIFFRACTION	2.79
7VF2	Human m6A-METTL associated complex (WTAP, VIRMA, ZC3H13, and HAKAI)	ELECTRON MICROSCOPY	3
7VF5	Human m6A-METTL associated complex (WTAP, VIRMA, and HAKAI)	ELECTRON MICROSCOPY	3
7YG4	Structure of WTAP-VIRMA in the m6A writer complex	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15007-F1	72.41	0.34

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear speckles

Antibody reliability (HPA): IH supported · IF enhanced

Functional residue map

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

Post-translational modifications (7)

Type	Positions
Phosphoserine	305, 306, 341, 388, 14
Phosphothreonine	350
N-acetylmethionine	1

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 2; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

2 pathways:

ID	Pathway	Evidence
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA	curated
R-HSA-8953854	Metabolism of RNA	—

MSigDB gene sets: 282 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, HORIUCHI_WTAP_TARGETS_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GNF2_BNIP2, PAL_PRMT5_TARGETS_UP, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, TGACCTY_ERR1_Q2, XU_HGF_SIGNALING_NOT_VIA_AKT1_48HR_DN, GOBP_MRNA_MODIFICATION, PUJANA_CHEK2_PCC_NETWORK, GTGCCTT_MIR506, AGTCTTA_MIR499, chr6q25, CATTTCA_MIR203

GO Biological Process (4): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA processing (GO:0006397), RNA splicing (GO:0008380), mRNA modification (GO:0016556)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear speck (GO:0016607), nuclear membrane (GO:0031965), RNA N6-methyladenosine methyltransferase complex (GO:0036396)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Metabolism of RNA	1

GO top-level categories

16 GO namespaces:

Category	Terms
RNA processing	2
mRNA metabolic process	2
cellular anatomical structure	2
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
RNA modification	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1
nucleus	1
nuclear envelope	1
organelle membrane	1
methyltransferase complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
mRNA processing	BP	mutant phenotype
regulation of alternative mRNA splicing, via spliceosome	BP	mutant phenotype
RNA N6-methyladenosine methyltransferase complex	CC	direct assay
nuclear membrane	CC	direct assay
nuclear speck	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,767 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WTAP	METTL14	Q9HCE5	942
WTAP	METTL3	Q86U44	935
WTAP	VIRMA	Q69YN4	923
WTAP	ALKBH5	Q6P6C2	923
WTAP	YTHDF1	Q9BYJ9	923
WTAP	FTO	Q9C0B1	923
WTAP	ZC3H13	Q5T200	922
WTAP	YTHDC1	Q96MU7	921
WTAP	METTL16	Q86W50	910
WTAP	YTHDC2	Q9H6S0	905
WTAP	RBM15B	Q8NDT2	905
WTAP	RBM15	Q96T37	905
WTAP	YTHDF2	Q9Y5A9	899
WTAP	YTHDF3	Q7Z739	898
WTAP	CBLL1	Q75N03	851

IntAct

Human interaction partners of WTAP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

20 partners by confidence:

Partner	Interaction type	MIscore	Records
VPS52	physical association	0.720	6
IKZF1	physical association	0.670	9
MAGEA11	physical association	0.670	4
SLIRP	physical association	0.670	3
ABHD15	physical association	0.560	3
BYSL	physical association	0.560	3
PSMA1	physical association	0.560	3
TCF12	physical association	0.560	3
TNIP1	physical association	0.560	3
WT1	physical association	0.560	3
ZNF239	physical association	0.560	3
ZNF572	physical association	0.560	3
YWHAZ	physical association	0.560	1
METTL3	association	0.530	3
METTL14	association	0.530	2
TAB1	physical association	0.370	1
DDX39A	association	0.350	1
RBM15B	association	0.350	1
TRIM28	association	0.350	1
VIRMA	association	0.350	1

BioGRID (2,572 interactions; top human partners by supporting records in a sample of 600 records): KIAA1429 (Co-fractionation; 7 records), METTL3 (Affinity Capture-MS; 6 records), WT1 (Affinity Capture-Western; 5 records), IKZF1 (Two-hybrid; 4 records), ZC3H13 (Co-fractionation; 4 records), ACTC1 (Affinity Capture-MS; 3 records), BCL6 (Co-localization; 3 records), CA4 (Affinity Capture-MS; 3 records), CBLL1 (Co-fractionation; 3 records), DDX39B (Affinity Capture-MS; 3 records), FAM175A (Affinity Capture-MS; 3 records), OGT (Reconstituted Complex; 3 records), USP7 (Affinity Capture-MS; 3 records), VPS52 (Two-hybrid; 3 records), ZNF645 (Affinity Capture-MS; 3 records)

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
CEN complex	37	SUPT16H, BMI1, CENPC, CENPU, FBL, RNF2, COBLL1, CUL4A, DDB1, HSPA5, NUP93, KIF23, ZFP91, CENPI, CENPK, RACGAP1, SSRP1, ZC3H13, CENPH, CENPM, HSPA8, VIRMA, CBX3, CENPB, SMARCA5, SRRT, CBX8, CENPA, CENPO, PLPPR3, RSF1, WDR11, WTAP, CENPL, DHX38, RING1, SHCBP1
m(6)A methyltransferase complex	6	METTL3, VIRMA, WTAP, ZC3H13, CBLL1, METTL14
METTL3-METTL14-WTAP complex	3	METTL14, METTL3, WTAP

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 20 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Metabolism of RNA	5	14.9×	2e-03

Disease & clinical

Genetic variants

Variant evidence for WTAP: 2 GWAS associations.

ClinVar

No ClinVar records for this gene.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 670):

Position(s)	Effect	Δscore	Sites
6:159736296–159736297	donor_loss	1.0000	4
6:159738988–159738989	acceptor_loss	1.0000	3
6:159739030	donor_gain	1.0000
6:159739046–159739047	donor_loss	1.0000	5
6:159742086–159742087	acceptor_loss	1.0000	3
6:159743654	acceptor_gain	1.0000
6:159743658	acceptor_gain	1.0000
6:159743661	acceptor_gain	1.0000
6:159743663	acceptor_loss	1.0000	2
6:159743793–159743794	donor_loss	1.0000	2

AlphaMissense

1,190 missense substitutions predicted likely pathogenic (of 2,622 scored), across 238 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M158	9	0.983	1.000
M218	9	0.966	0.999
M78	9	0.958	0.999
M163	9	0.875	0.992
N168	8	1.000	1.000
F147	8	0.998	1.000
D114	8	0.995	0.999
D212	8	0.994	0.999
D150	8	0.993	0.999
S151	8	0.992	1.000
F207	8	0.977	0.999
D202	8	0.955	0.991
N74	8	0.940	0.995
D206	8	0.927	0.988
F121	8	0.923	0.997
N205	8	0.890	0.997
M87	8	0.887	0.994
D51	8	0.878	0.975
D17	8	0.872	0.968
C161	7	0.999	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	1.23e-06
Ovary Serous Cystadenocarcinoma (TCGA)	unfavorable	3.45e-05
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000123

Disease associations

OMIM: gene MIM:605442 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST006218_106	Erosive tooth wear (severe vs non-severe)	3e-8
GCST000301_1	Iron status biomarkers	1e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004461	iron biomarker measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523298 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases expression, affects expression, decreases expression	7
Valproic Acid	affects expression, decreases expression, decreases methylation	5
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	increases expression, decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
TL8-506	increases expression, affects cotreatment	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
nickel sulfate	decreases expression	1
cadmium sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
CC-8490	increases expression	1
abrine	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Amiodarone	increases expression	1
Arsenic	increases expression	1
Benzo(a)pyrene	increases expression	1
Cobalt	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4379086	Binding	Binding affinity to WTAP (unknown origin) at protein to compound concentration ratio of 1:20 by differential scanning fluorimetry	Discovery of 4H-Chromen-4-one Derivatives as a New Class of Selective Rho Kinase (ROCK) Inhibitors, which Showed Potent Activity in ex Vivo Diabetic Retinopathy Models. — *J Med Chem*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TY23	HAP1 WTAP (-) 1	Cancer cell line	Male
CVCL_TY24	HAP1 WTAP (-) 2	Cancer cell line	Male
CVCL_TY25	HAP1 WTAP (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.