WDR54

Summary

WDR54 (WD repeat domain 54, HGNC:25770) is a protein-coding gene on chromosome 2p13.1, encoding WD repeat-containing protein 54 (Q9H977). Plays a role in the adhesion and fusion of the sperm-oocyte membrane through its interactions with IZUMO1 and IZUMO1R/JUNO.

Enables protein homodimerization activity. Involved in negative regulation of receptor internalization; regulation of MAPK cascade; and regulation of epidermal growth factor receptor signaling pathway. Located in vesicle.

Source: NCBI Gene 84058 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 81 total
• MANE Select transcript: NM_032118

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25770
Approved symbol	WDR54
Name	WD repeat domain 54
Location	2p13.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12953
Ensembl gene	ENSG00000005448
Ensembl biotype	protein_coding
OMIM	620826
Entrez	84058

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 19 protein_coding, 8 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000348227, ENST00000409791, ENST00000461531, ENST00000465134, ENST00000468778, ENST00000469321, ENST00000469932, ENST00000475328, ENST00000480089, ENST00000482605, ENST00000482880, ENST00000493982, ENST00000861017, ENST00000861018, ENST00000861019, ENST00000861020, ENST00000917846, ENST00000917847, ENST00000917848, ENST00000917849, ENST00000917850, ENST00000917851, ENST00000917852, ENST00000917853, ENST00000917854, ENST00000917855, ENST00000960088, ENST00000960089, ENST00000960090

RefSeq mRNA: 4 — MANE Select: NM_032118 NM_001320823, NM_001320824, NM_001320825, NM_032118

CCDS: CCDS1940, CCDS82473

Canonical transcript exons

ENST00000348227 — 10 exons

Exon	Start	End
ENSE00001642537	74421730	74421816
ENSE00003460339	74425075	74425237
ENSE00003467978	74424875	74424975
ENSE00003507821	74423855	74423982
ENSE00003517651	74425417	74425491
ENSE00003523078	74423319	74423385
ENSE00003569510	74422870	74422932
ENSE00003653351	74422153	74422375
ENSE00003660973	74425570	74425755
ENSE00003681747	74423478	74423531

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7452 / max 239.3121, expressed in 1700 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21022	25.6792	1699
21023	0.4466	222
21021	0.3690	189
202243	0.2504	129

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	99.04	gold quality
right uterine tube	UBERON:0001302	98.73	gold quality
bronchus	UBERON:0002185	98.44	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.47	gold quality
ventricular zone	UBERON:0003053	94.40	gold quality
left testis	UBERON:0004533	92.84	gold quality
right testis	UBERON:0004534	92.68	gold quality
oviduct epithelium	UBERON:0004804	92.59	gold quality
pituitary gland	UBERON:0000007	92.31	gold quality
adenohypophysis	UBERON:0002196	92.31	gold quality
fallopian tube	UBERON:0003889	92.13	gold quality
testis	UBERON:0000473	91.57	gold quality
tibial nerve	UBERON:0001323	90.93	gold quality
epithelium of nasopharynx	UBERON:0001951	90.73	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.64	gold quality
prefrontal cortex	UBERON:0000451	90.00	gold quality
ganglionic eminence	UBERON:0004023	89.96	gold quality
cortical plate	UBERON:0005343	89.91	gold quality
adult organism	UBERON:0007023	89.24	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.21	gold quality
middle temporal gyrus	UBERON:0002771	89.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.96	gold quality
right frontal lobe	UBERON:0002810	88.93	gold quality
nucleus accumbens	UBERON:0001882	88.69	gold quality
hypothalamus	UBERON:0001898	88.50	gold quality
caudate nucleus	UBERON:0001873	88.29	gold quality
anterior cingulate cortex	UBERON:0009835	88.18	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.01	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.95	gold quality
cerebellar hemisphere	UBERON:0002245	87.93	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	62.95
E-HCAD-1	yes	26.49
E-MTAB-10287	yes	25.20
E-GEOD-130148	yes	10.95
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• WDR54 was found to be elevated and associated with prognosis in patients with colorectal cancer (CRC). Functional assays showed that WDR54 facilitates the aggressiveness of CRC cells and promotes tumor growth in mice. Knockdown of WDR54 sensitizes CRC cells to the proliferation-inhibitory effect of SHP2 inhibitor, an effect involving their common function in regulating AKT and ERK signaling. (PMID:29987896)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wdr54	ENSDARG00000010248
mus_musculus	Wdr54	ENSMUSG00000030032
rattus_norvegicus	Wdr54	ENSRNOG00000009324
caenorhabditis_elegans		WBGENE00004767

Paralogs (14): FBXW11 (ENSG00000072803), FBXW7 (ENSG00000109670), TRAF7 (ENSG00000131653), FBXW9 (ENSG00000132004), FBXO36 (ENSG00000153832), WDR64 (ENSG00000162843), FBXW12 (ENSG00000164049), BTRC (ENSG00000166167), WDR49 (ENSG00000174776), FBXW8 (ENSG00000174989), PAAF1 (ENSG00000175575), WDR86 (ENSG00000187260), FBXO16 (ENSG00000214050), EFCAB8 (ENSG00000215529)

Protein

Protein identifiers

WD repeat-containing protein 54 — Q9H977 (reviewed: Q9H977)

All UniProt accessions (1): Q9H977

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the adhesion and fusion of the sperm-oocyte membrane through its interactions with IZUMO1 and IZUMO1R/JUNO. When cross-linked to form dimers and trimers, it has a regulatory effect on ERK signaling pathway activity in response to EGF stimulation. Colocalizes with the EGF receptor in WDR54-specific vesicle where it sustains the internalization and controls the degradation of the EGF receptor after EGF stimulation.

Subunit / interactions. Homodimer and homotrimer; forms tight forms of dimers and trimers. Interacts with IZUMO1 and IZUMO1R/JUNO.

Subcellular location. Vesicle. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in epithelial cells (at protein level). Isoform 3 expression is highly increased in colorectal cancer cells.

Post-translational modifications. Cross-linked to tightly form both dimers and trimers by TGM2. Cross-linking enhances the activation of EGF receptor-mediated signaling pathway. Cross-linking is inhibited by EGF. Ubiquitinated. EGF increases ubiquitination.

Domain organisation. WD6 repeat is required for cross-linking by TGM2.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H977-1	1, b	yes
Q9H977-3	3, c
Q9H977-4	2, a

RefSeq proteins (4): NP_001307752, NP_001307753, NP_001307754, NP_115494* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR049546	WDR54_beta_prop	Domain

Pfam: PF21031

UniProt features (15 total): mutagenesis site 6, splice variant 4, repeat 3, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H977-F1	93.08	0.84

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
221	decreases cross-linking.
279	abolishes cross-linking. decreases erk signaling pathway activation. abolishes inhibition of egf receptor degradation af
280	decreases cross-linking. abolishes ubiquitination.
304	no effect on cross-linking.
107	decreases cross-linking.
196	slightly decreases cross-linking.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 127 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_SINGLE_FERTILIZATION, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, MENSE_HYPOXIA_UP, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_RECEPTOR_INTERNALIZATION, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, GOBP_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS

GO Biological Process (5): negative regulation of receptor internalization (GO:0002091), single fertilization (GO:0007338), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), regulation of epidermal growth factor receptor signaling pathway (GO:0042058), regulation of MAPK cascade (GO:0043408)

GO Molecular Function (2): protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), motile cilium (GO:0031514), vesicle (GO:0031982), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulation of receptor internalization	1
receptor internalization	1
negative regulation of receptor-mediated endocytosis	1
fertilization	1
single fertilization	1
cellular process involved in reproduction in multicellular organism	1
epidermal growth factor receptor signaling pathway	1
regulation of ERBB signaling pathway	1
MAPK cascade	1
regulation of intracellular signal transduction	1
identical protein binding	1
protein dimerization activity	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cilium	1
membrane-bounded organelle	1

Protein interactions and networks

STRING

434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WDR54	CCDC142	Q17RM4	555
WDR54	ITPRIPL1	Q6GPH6	549
WDR54	INO80B	Q9C086	477
WDR54	WDR53	Q7Z5U6	469
WDR54	CCDC140	Q96MF4	449
WDR54	C2orf81	A6NN90	447
WDR54	LBX2	Q6XYB7	445
WDR54	WDR55	Q9H6Y2	436
WDR54	ZCRB1	Q8TBF4	432
WDR54	ZZEF1	O43149	428
WDR54	CCDC107	Q8WV48	428
WDR54	FAAP100	Q0VG06	420
WDR54	MOGS	Q13724	419
WDR54	DQX1	Q8TE96	401
WDR54	TTC31	Q49AM3	397

IntAct

61 interactions, top by confidence:

A	B	Type	Score
GYG2	GYS1	psi-mi:“MI:0914”(association)	0.660
BCL7A	ARID1A	psi-mi:“MI:0914”(association)	0.640
BCL7C	ARID1A	psi-mi:“MI:0914”(association)	0.640
CHCHD4	SSNA1	psi-mi:“MI:0914”(association)	0.640
MAPK8IP3	RCCD1	psi-mi:“MI:0914”(association)	0.640
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
MPDZ	SMCHD1	psi-mi:“MI:0914”(association)	0.590
WDR54	MEMO1	psi-mi:“MI:0915”(physical association)	0.560
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
TKT	POTEF	psi-mi:“MI:0914”(association)	0.530
LCN15	POTEF	psi-mi:“MI:0914”(association)	0.530
MAPK8IP3	DCTN6	psi-mi:“MI:0914”(association)	0.530
USP16	HERC2	psi-mi:“MI:0914”(association)	0.530
DMD	UTRN	psi-mi:“MI:0914”(association)	0.530
TRAK1	MTX2	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
DOK3	BLTP3B	psi-mi:“MI:0914”(association)	0.350
BCL7A	DPF1	psi-mi:“MI:0914”(association)	0.350
BCL7C	DPF1	psi-mi:“MI:0914”(association)	0.350
APEX2	CUL7	psi-mi:“MI:0914”(association)	0.350
CLEC3A	ZNF593	psi-mi:“MI:0914”(association)	0.350
DMD	DTNB	psi-mi:“MI:0914”(association)	0.350
ACP7	MYCBP2	psi-mi:“MI:0914”(association)	0.350
GMEB1	MATN4	psi-mi:“MI:0914”(association)	0.350
USP16	HERC2	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): WDR54 (Two-hybrid), WDR54 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), FLYWCH2 (Affinity Capture-MS), OSCP1 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), OSCP1 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), FLYWCH2 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), WDR54 (Affinity Capture-MS)

ESM2 similar proteins: A5DNK9, A8ID74, A8IF44, A8IRK7, A8J1V4, A8JAF2, A8JAN3, A8JFU2, A9UP22, C4YBE4, D3ZX63, O75843, P0DKL4, P0DKL6, P93043, P93231, Q09417, Q15269, Q1LVE8, Q24314, Q28205, Q2TAF3, Q3V3N7, Q57WH1, Q5DM57, Q5RFQ3, Q5TTP0, Q5XUX1, Q5ZHX9, Q6C462, Q6C953, Q6CAH5, Q74ZJ1, Q7TT37, Q8BU03, Q8CFJ9, Q8NFJ9, Q8R307, Q96S15, Q9H977

Diamond homologs: D3ZX63, Q9H977, Q9R0D8, O42948

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1216 predictions. Top by Δscore:

Variant	Effect	Δscore
2:74422848:ACACT:A	acceptor_gain	1.0000
2:74422850:A:AG	acceptor_gain	1.0000
2:74422850:ACT:A	acceptor_gain	1.0000
2:74422851:C:G	acceptor_gain	1.0000
2:74423980:CAGG:C	donor_loss	1.0000
2:74423983:G:A	donor_loss	1.0000
2:74423984:T:G	donor_loss	1.0000
2:74425073:A:AG	acceptor_gain	1.0000
2:74425074:G:GG	acceptor_gain	1.0000
2:74425074:GA:G	acceptor_gain	1.0000
2:74425234:CAAGG:C	donor_loss	1.0000
2:74425238:G:C	donor_loss	1.0000
2:74425239:T:A	donor_loss	1.0000
2:74425413:A:AG	acceptor_gain	1.0000
2:74425414:C:G	acceptor_gain	1.0000
2:74425415:A:AG	acceptor_gain	1.0000
2:74425415:A:G	acceptor_loss	1.0000
2:74425416:G:GT	acceptor_gain	1.0000
2:74425416:GC:G	acceptor_gain	1.0000
2:74425416:GCT:G	acceptor_gain	1.0000
2:74425416:GCTA:G	acceptor_gain	1.0000
2:74425416:GCTAC:G	acceptor_gain	1.0000
2:74425490:AGGTA:A	donor_loss	1.0000
2:74425492:G:GG	donor_gain	1.0000
2:74425492:GT:G	donor_loss	1.0000
2:74425493:T:A	donor_loss	1.0000
2:74425565:CCCAG:C	acceptor_loss	1.0000
2:74425566:CCAG:C	acceptor_loss	1.0000
2:74425568:A:AG	acceptor_gain	1.0000
2:74425568:A:AT	acceptor_loss	1.0000

AlphaMissense

2141 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:74425453:T:A	W279R	0.989
2:74425453:T:C	W279R	0.989
2:74425435:G:C	D273H	0.986
2:74425625:T:C	F310S	0.984
2:74425624:T:C	F310L	0.983
2:74425626:T:A	F310L	0.983
2:74425626:T:G	F310L	0.983
2:74424926:T:A	W196R	0.979
2:74424926:T:C	W196R	0.979
2:74424897:C:A	T186K	0.978
2:74425436:A:T	D273V	0.975
2:74425436:A:C	D273A	0.974
2:74422213:C:A	N20K	0.973
2:74422213:C:G	N20K	0.973
2:74424899:G:C	A187P	0.973
2:74425652:C:A	A319D	0.973
2:74422876:T:A	W77R	0.972
2:74422876:T:C	W77R	0.972
2:74423531:G:A	G136R	0.972
2:74423531:G:C	G136R	0.972
2:74423882:T:C	F145S	0.972
2:74423855:G:A	G136E	0.971
2:74425418:T:C	L267P	0.971
2:74425455:G:C	W279C	0.971
2:74425455:G:T	W279C	0.971
2:74422928:T:A	I94K	0.970
2:74424894:T:A	V185E	0.970
2:74425649:T:C	F318S	0.969
2:74425651:G:C	A319P	0.969
2:74425421:T:A	L268H	0.968

dbSNP variants (sampled 300 via entrez): RS1000899475 (2:74425076 G>C), RS1002394532 (2:74425347 C>G), RS1002448553 (2:74425594 G>A), RS1002510898 (2:74420131 C>A), RS1002607428 (2:74421694 G>C), RS1003660238 (2:74422741 C>A,T), RS1004461004 (2:74421633 G>A,C,T), RS1004470860 (2:74421397 G>A,T), RS1004471688 (2:74421163 T>C), RS1005459833 (2:74423252 G>A,T), RS1005743830 (2:74422493 C>A,T), RS1006131301 (2:74424294 C>A,G), RS1006474278 (2:74424496 T>G), RS1007447505 (2:74422805 A>C,G), RS1008205188 (2:74424439 G>A)

Disease associations

OMIM: gene MIM:620826 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009927_1	Stress urinary incontinence	5.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Smoke	increases expression, decreases expression, increases abundance	3
Tobacco Smoke Pollution	decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cisplatin	affects expression, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects expression	1
glycidyl methacrylate	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	affects expression	1
Decitabine	affects expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1

Clinical trials (associated diseases)

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