WDFY4

gene
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Also known as KIAA1607Em:AC060234.3FLJ45748

Summary

WDFY4 (WDFY family member 4, HGNC:29323) is a protein-coding gene on chromosome 10q11.23, encoding WD repeat- and FYVE domain-containing protein 4 (Q6ZS81). Plays a critical role in the regulation of cDC1-mediated cross-presentation of viral and tumor antigens in dendritic cells.

Predicted to be involved in antigen processing and presentation. Predicted to act upstream of or within with a positive effect on CD8-positive, alpha-beta T cell activation. Predicted to act upstream of or within cellular response to virus. Predicted to be located in early endosome and endoplasmic reticulum.

Source: NCBI Gene 57705 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
  • GWAS associations: 21
  • Clinical variants (ClinVar): 554 total
  • Druggable target: yes
  • MANE Select transcript: NM_001394531

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:29323
Approved symbolWDFY4
NameWDFY family member 4
Location10q11.23
Locus typegene with protein product
StatusApproved
AliasesKIAA1607, Em:AC060234.3, FLJ45748
Ensembl geneENSG00000128815
Ensembl biotypeprotein_coding
OMIM613316
Entrez57705

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000325239, ENST00000360890, ENST00000374161, ENST00000465910, ENST00000490507, ENST00000497480, ENST00000858472

RefSeq mRNA: 3 — MANE Select: NM_001394531 NM_001370154, NM_001394531, NM_020945

CCDS: CCDS44385, CCDS91241

Canonical transcript exons

ENST00000325239 — 62 exons

ExonStartEnd
ENSE000012284744870971648709966
ENSE000016038474876034748760440
ENSE000016140394878853048788675
ENSE000016410254873588048736070
ENSE000016472614874296848743548
ENSE000016943514878663948786870
ENSE000017158604877861148778832
ENSE000017175904877445848774672
ENSE000017190804879072748790917
ENSE000017693654877994148780119
ENSE000017804324877675048776984
ENSE000017884374879629848796450
ENSE000017999614877741948777495
ENSE000018021124878987448789985
ENSE000018042464877571248775806
ENSE000035598524898250948982956
ENSE000037917404896384248964054
ENSE000037918054889057948890727
ENSE000037923794887703348877199
ENSE000037926284880328648803359
ENSE000037930244897830948978393
ENSE000037931434883257348832709
ENSE000037935224880785948807958
ENSE000037935264895972248959813
ENSE000037936974897013148970289
ENSE000037937794882667148826909
ENSE000037938434897486248975041
ENSE000037947124882877848828896
ENSE000037951954881053048810735
ENSE000037959004894604048946157
ENSE000037959604887508948875140
ENSE000037964464882023448820437
ENSE000037964604894333048943449
ENSE000037965614894686048946969
ENSE000037966254880526048805421
ENSE000037967124886726548867342
ENSE000037970644881395748814082
ENSE000037971494896906448969248
ENSE000037971854880600448806095
ENSE000037971954896652648966673
ENSE000037978604889745448897574
ENSE000037981484895712948957282
ENSE000037982754898136748981478
ENSE000037987004890022148900306
ENSE000037988574897679748976979
ENSE000037992844894180648941848
ENSE000037993574887349148873697
ENSE000038000994882106248821176
ENSE000038001504883070048830885
ENSE000038002414882238048822537
ENSE000038006344890180148901863
ENSE000038007634881153948811708
ENSE000038008024881724548817409
ENSE000038046974873393148734035
ENSE000038055754872943248729589
ENSE000038059194873111048731562
ENSE000038083994872343348723567
ENSE000038087514872747048727659
ENSE000038091804872126148721367
ENSE000038095864872001148720125
ENSE000038104354872588148726070
ENSE000039372284868487348685001

Expression profiles

Bgee: expression breadth ubiquitous, 186 present calls, max score 91.95.

FANTOM5 (CAGE): breadth broad, TPM avg 9.2045 / max 423.3553, expressed in 487 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter IDTPM avgSamples expressed
1048596.3969430
1048581.2880299
1048600.8073198
1048570.2054111
1048610.145274
1048620.130759
2058620.06171
1048700.057722
1048630.056126
1048690.043619

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
superficial temporal arteryUBERON:000161491.95silver quality
lymph nodeUBERON:000002989.43gold quality
spleenUBERON:000210689.36gold quality
granulocyteCL:000009487.94gold quality
bone marrow cellCL:000209287.30gold quality
bloodUBERON:000017887.25gold quality
vermiform appendixUBERON:000115485.52gold quality
ileal mucosaUBERON:000033185.06gold quality
leukocyteCL:000073884.99gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047384.89gold quality
monocyteCL:000057684.74gold quality
spermCL:000001983.34silver quality
trabecular bone tissueUBERON:000248383.17gold quality
bone marrowUBERON:000237180.72gold quality
caecumUBERON:000115380.57gold quality
tonsilUBERON:000237280.43gold quality
buccal mucosa cellCL:000233679.22silver quality
visceral pleuraUBERON:000240179.20silver quality
epithelium of nasopharynxUBERON:000195178.68gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099178.22gold quality
upper arm skinUBERON:000426377.34gold quality
parietal pleuraUBERON:000240076.13silver quality
small intestine Peyer’s patchUBERON:000345475.25gold quality
myocardiumUBERON:000234974.94gold quality
palpebral conjunctivaUBERON:000181274.69gold quality
right lungUBERON:000216774.69gold quality
gall bladderUBERON:000211074.48gold quality
kidney epitheliumUBERON:000481974.48gold quality
left testisUBERON:000453374.46gold quality
upper lobe of left lungUBERON:000895273.96gold quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-MTAB-9801yes2704.26
E-MTAB-6678yes1787.05
E-CURD-120yes585.02
E-HCAD-1yes21.55
E-MTAB-6701yes21.38
E-ANND-3yes13.98
E-MTAB-8498yes12.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

24 targeting WDFY4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-3163100.0077.238605
HSA-MIR-146A-5P99.9668.93988
HSA-MIR-146B-5P99.9669.13977
HSA-MIR-4666A-3P99.9671.713434
HSA-MIR-7153-5P99.9468.891006
HSA-MIR-4659A-3P99.8072.624248
HSA-MIR-4659B-3P99.8072.624248
HSA-MIR-148A-3P99.7473.771700
HSA-MIR-148B-3P99.7473.751700
HSA-MIR-152-3P99.7473.751703
HSA-MIR-7161-5P99.6868.921592
HSA-MIR-548U99.6567.781463
HSA-MIR-318299.4068.152454
HSA-MIR-4687-5P99.1466.26488
HSA-MIR-129-1-3P98.8668.41779
HSA-MIR-129-2-3P98.8668.41779
HSA-MIR-6829-5P98.8665.121480
HSA-MIR-429098.5165.17907
HSA-MIR-5008-5P98.4265.871019
HSA-MIR-1022698.2566.50811
HSA-MIR-6779-3P97.5165.82789
HSA-MIR-93897.4168.28656
HSA-MIR-158796.9564.03932
HSA-MIR-365195.6264.67287

Literature-anchored findings (GeneRIF, showing 7)

  • Genetic variants in ETS1 and WDFY4 were found to be associated with systemic lupus erythematosus, in the Asian population studied. (PMID:20169177)
  • rs877819 SNP in WDFY4 may be associated with systemic lupus erythematosus by reduced binding of YY1 and downregulating WDFY4 expression. (PMID:22972472)
  • A significantly increased risk for RA associated with the WDFY4 rs7097397 AG genotype. (PMID:24549174)
  • We identified a variant in WDFY4 that was significantly associated with clinically amyopathic dermatomyositis (CADM). This variant had a cis-splicing quantitative trait locus effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. (PMID:29331962)
  • BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes. (PMID:33189404)
  • Analysis of WDFY4 rs7097397 and PHLDB1 rs7389 polymorphisms in Chinese patients with systemic lupus erythematosus. (PMID:35188604)
  • WDFY4 polymorphisms in Chinese patients with anti-MDA5 dermatomyositis is associated with rapid progressive interstitial lung disease. (PMID:36637178)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_reriowdfy4ENSDARG00000077009
mus_musculusWdfy4ENSMUSG00000051506
rattus_norvegicusWdfy4ENSRNOG00000029662
caenorhabditis_elegansWBGENE00004760
caenorhabditis_elegansWBGENE00007752

Paralogs (7): NSMAF (ENSG00000035681), LYST (ENSG00000143669), NBEAL1 (ENSG00000144426), NBEAL2 (ENSG00000160796), WDFY3 (ENSG00000163625), NBEA (ENSG00000172915), LRBA (ENSG00000198589)

Protein

Protein identifiers

WD repeat- and FYVE domain-containing protein 4Q6ZS81 (reviewed: Q6ZS81)

All UniProt accessions (2): Q6ZS81, A0A1W2PQ91

UniProt curated annotations — full annotation on UniProt →

Function. Plays a critical role in the regulation of cDC1-mediated cross-presentation of viral and tumor antigens in dendritic cells. Mechanistically, acts near the plasma membrane and interacts with endosomal membranes to promote endosomal-to-cytosol antigen trafficking. Also plays a role in B-cell survival through regulation of autophagy.

Subunit / interactions. Interacts with HSP90AB1.

Subcellular location. Early endosome. Endoplasmic reticulum.

Isoforms (5)

UniProt IDNamesCanonical?
Q6ZS81-11yes
Q6ZS81-22
Q6ZS81-33
Q6ZS81-44
Q6ZS81-55

RefSeq proteins (3): NP_001357083, NP_001381460, NP_065996 (=MANE)

Domains & families (InterPro)

IDNameType
IPR000409BEACH_domDomain
IPR001680WD40_rptRepeat
IPR011989ARM-likeHomologous_superfamily
IPR011993PH-like_dom_sfHomologous_superfamily
IPR015943WD40/YVTN_repeat-like_dom_sfHomologous_superfamily
IPR016024ARM-type_foldHomologous_superfamily
IPR019775WD40_repeat_CSConserved_site
IPR023362PH-BEACH_domDomain
IPR036322WD40_repeat_dom_sfHomologous_superfamily
IPR036372BEACH_dom_sfHomologous_superfamily
IPR051944BEACH_domain_proteinFamily

Pfam: PF00400, PF02138

UniProt features (31 total): splice variant 7, repeat 6, region of interest 5, sequence conflict 4, compositionally biased region 3, sequence variant 3, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q6ZS81 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 123 (showing top): GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION, TGANTCA_AP1_C, GOBP_ALPHA_BETA_T_CELL_ACTIVATION, RYTTCCTG_ETS2_B, ELK1_01, P300_01, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, NERF_Q2, GOBP_RESPONSE_TO_VIRUS, PASQUALUCCI_LYMPHOMA_BY_GC_STAGE_DN, MGGAAGTG_GABP_B, CHEN_METABOLIC_SYNDROM_NETWORK, GOBP_LYMPHOCYTE_ACTIVATION

GO Biological Process (4): autophagy (GO:0006914), antigen processing and presentation (GO:0019882), CD8-positive, alpha-beta T cell activation (GO:0036037), cellular response to virus (GO:0098586)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): early endosome (GO:0005769), endoplasmic reticulum (GO:0005783), endosome (GO:0005768)

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
endomembrane system2
catabolic process1
transmembrane transport1
process utilizing autophagic mechanism1
immune system process1
alpha-beta T cell activation1
response to virus1
binding1
endosome1
cytoplasm1
intracellular membrane-bounded organelle1
cytoplasmic vesicle1

Protein interactions and networks

STRING

2802 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
WDFY4LRRC18Q8N456700
WDFY4WDFY2Q96P53578
WDFY4SNX22Q96L94544
WDFY4WDFY1Q8IWB7522
WDFY4IFIH1Q9BYX4490
WDFY4BANK1Q8NDB2487
WDFY4RCCD1A6NED2469
WDFY4TLR9Q9NR96458
WDFY4TMEM208Q9BTX3453
WDFY4TLR3O15455441
WDFY4BATF3Q9NR55432
WDFY4LAPTM5Q13571430
WDFY4MYCBP2O75592427
WDFY4MPPE1Q53F39426
WDFY4SEC22BO75396425

IntAct

5 interactions, top by confidence:

ABTypeScore
WDFY4PLOD1psi-mi:“MI:0915”(physical association)0.400
APBB1SSPOPpsi-mi:“MI:0914”(association)0.350
NTRK1ILVBLpsi-mi:“MI:0914”(association)0.350
WDFY4tktApsi-mi:“MI:0915”(physical association)0.000

BioGRID (7): WDFY4 (Proximity Label-MS), WDFY4 (Affinity Capture-MS), HSPA8 (Cross-Linking-MS (XL-MS)), WDFY4 (Proximity Label-MS), WDFY4 (Affinity Capture-MS), WDFY4 (Affinity Capture-RNA), WDFY4 (Affinity Capture-MS)

ESM2 similar proteins: A0JMW6, A1L1L2, A1L2I9, A2A9C3, A4FV45, A8C756, B0I564, D3ZND0, E9Q2M9, G3HQ82, O15360, O35821, O70576, O75800, Q15021, Q1JPG0, Q24JP3, Q4KLN4, Q5T011, Q5U1Z0, Q5U249, Q66H56, Q6AXZ5, Q6GPP1, Q6NUQ4, Q6NXR4, Q6ZS81, Q7L4E1, Q8BGI5, Q8BK03, Q8BM55, Q8BMG7, Q8BTG3, Q8C3S2, Q8CJF7, Q8K2Z4, Q8K368, Q8WYP5, Q92574, Q99M76

Diamond homologs: A8XSV3, D4A929, E7FAW3, E9Q2M9, F4HZB2, F4IG73, F4JD14, F4JHT3, O35242, P0C6P0, P25356, P50851, P97412, Q19317, Q54PP7, Q54RQ8, Q55AV3, Q55DM1, Q562E7, Q5ND34, Q6VNB8, Q6ZNJ1, Q6ZQA0, Q6ZS30, Q6ZS81, Q7LKZ7, Q86JF2, Q8IZQ1, Q8NFP9, Q92636, Q99698, Q9DDD5, Q9EPN1, Q9ESE1, Q9TTK4, Q9W060, Q9W4E2, E7FEV0, F4I9T0, F4JY12

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance469
Likely benign42
Benign13

Top pathogenic / likely-pathogenic (0)

SpliceAI

10723 predictions. Top by Δscore:

VariantEffectΔscore
10:48709965:AGGTT:Adonor_loss1.0000
10:48723512:T:TAacceptor_gain1.0000
10:48723565:CAGG:Cdonor_loss1.0000
10:48723567:GGT:Gdonor_loss1.0000
10:48723568:G:GCdonor_loss1.0000
10:48723569:T:Adonor_loss1.0000
10:48725879:A:AGacceptor_gain1.0000
10:48725879:AGAT:Aacceptor_gain1.0000
10:48725880:G:GAacceptor_gain1.0000
10:48725880:G:GCacceptor_loss1.0000
10:48725880:GAT:Gacceptor_gain1.0000
10:48725880:GATG:Gacceptor_gain1.0000
10:48725880:GATGT:Gacceptor_gain1.0000
10:48725997:G:GTdonor_gain1.0000
10:48726060:G:GGdonor_gain1.0000
10:48726067:CAGGG:Cdonor_loss1.0000
10:48726069:GG:Gdonor_gain1.0000
10:48726070:GG:Gdonor_gain1.0000
10:48726071:GTAT:Gdonor_loss1.0000
10:48726072:T:Gdonor_loss1.0000
10:48727468:A:AGacceptor_gain1.0000
10:48727469:G:GAacceptor_gain1.0000
10:48727658:CGGTA:Cdonor_loss1.0000
10:48727659:GGTAA:Gdonor_loss1.0000
10:48727660:G:GGdonor_gain1.0000
10:48727660:GTAAG:Gdonor_loss1.0000
10:48727661:T:Gdonor_loss1.0000
10:48731108:AGG:Aacceptor_gain1.0000
10:48731109:GGG:Gacceptor_gain1.0000
10:48731534:G:GTdonor_gain1.0000

AlphaMissense

20855 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
10:48974928:A:CS2999R0.998
10:48974930:C:AS2999R0.998
10:48974930:C:GS2999R0.998
10:48941843:T:AW2542R0.997
10:48941843:T:CW2542R0.997
10:48941845:G:CW2542C0.997
10:48941845:G:TW2542C0.997
10:48943423:T:AW2575R0.997
10:48943423:T:CW2575R0.997
10:48982532:G:AG3171D0.997
10:48982558:T:AW3180R0.996
10:48982558:T:CW3180R0.996
10:48943347:T:AN2549K0.995
10:48943347:T:GN2549K0.995
10:48959769:T:AW2727R0.995
10:48959769:T:CW2727R0.995
10:48963881:T:AW2755R0.995
10:48963881:T:CW2755R0.995
10:48981462:G:CA3158P0.995
10:48810567:T:AW1626R0.994
10:48810567:T:CW1626R0.994
10:48969145:C:AA2889D0.994
10:48976978:G:CR3097P0.994
10:48780027:T:AW1162R0.993
10:48780027:T:CW1162R0.993
10:48897563:T:CF2476L0.993
10:48897565:C:AF2476L0.993
10:48897565:C:GF2476L0.993
10:48943386:A:CR2562S0.993
10:48943386:A:TR2562S0.993

dbSNP variants (sampled 300 via entrez): RS1000023381 (10:48931463 C>T), RS1000028419 (10:48973845 C>T), RS1000028490 (10:48770882 T>C), RS1000035752 (10:48806523 C>T), RS1000042724 (10:48821573 C>T), RS1000045285 (10:48845958 C>T), RS1000053469 (10:48859178 T>G), RS1000055905 (10:48968369 C>T), RS1000061102 (10:48748621 G>A), RS1000081782 (10:48974162 G>A,T), RS1000082851 (10:48924620 A>G), RS1000114558 (10:48810543 A>C,G,T), RS1000118694 (10:48865514 G>T), RS1000131428 (10:48901176 C>T), RS1000140397 (10:48691707 A>G,T)

Disease associations

OMIM: gene MIM:613316 | disease phenotypes:

GenCC curated gene-disease

DiseaseClassificationInheritance
complex neurodevelopmental disorderLimitedAutosomal recessive

Mondo (1): complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

StudyTraitp-value
GCST000216_2Systemic lupus erythematosus3.000000e-06
GCST000507_14Systemic lupus erythematosus7.000000e-12
GCST000592_2Systemic lupus erythematosus8.000000e-12
GCST001308_6Response to anti-depressant treatment in major depressive disorder2.000000e-07
GCST001795_25Systemic lupus erythematosus8.000000e-09
GCST002318_166Rheumatoid arthritis3.000000e-09
GCST002724_18Airway responsiveness in chronic obstructive pulmonary disease7.000000e-06
GCST002987_21Stroke9.000000e-08
GCST002987_9Stroke9.000000e-08
GCST003155_9Systemic lupus erythematosus5.000000e-09
GCST003156_2Systemic lupus erythematosus9.000000e-12
GCST003252_27Systemic lupus erythematosus1.000000e-06
GCST003599_11Systemic lupus erythematosus2.000000e-09
GCST003622_35Systemic lupus erythematosus9.000000e-11
GCST003622_65Systemic lupus erythematosus5.000000e-07
GCST005338_1Clinically amyopathic dermatomyositis2.000000e-08
GCST005752_132Systemic lupus erythematosus7.000000e-10
GCST006959_116Rheumatoid arthritis6.000000e-07
GCST007400_29Systemic lupus erythematosus1.000000e-08
GCST007843_19Rheumatoid arthritis3.000000e-08
GCST011956_40Systemic lupus erythematosus2.000000e-40

EFO canonical traits (3, from GWAS)

EFO IDTrait name
EFO:0006320antidepressant-induced side effect
EFO:0006897airway responsiveness measurement
EFO:0008532clinically amyopathic dermatomyositis

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4742299 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

ChemicalActions (top 5)PubMed papers
(+)-JQ1 compounddecreases expression2
Benzo(a)pyreneaffects methylation, decreases expression, increases methylation2
aflatoxin B2decreases methylation1
di-n-butylphosphoric acidaffects expression1
CGP 52608affects binding, increases reaction1
nutlin 3affects cotreatment, increases expression1
abrineincreases expression1
bisphenol Sdecreases methylation1
Air Pollutantsaffects expression, increases abundance1
Dactinomycinaffects cotreatment, increases expression1
Ethyl Methanesulfonatedecreases expression1
Formaldehydedecreases expression1
Methyl Methanesulfonatedecreases expression1
Nickelincreases expression1
Ozoneaffects expression, increases abundance1
Phthalic Acidsincreases methylation1
Tobacco Smoke Pollutiondecreases methylation1
Triclosanincreases expression1
Valproic Acidincreases methylation1
Antirheumatic Agentsdecreases expression1
Cadmium Chlorideincreases expression1
Magnetite Nanoparticlesincreases expression1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4713759BindingProtac activity at CRBN/WDFY4 in human BxPC-3 cells assessed as WDFY4 degradation incubated for 16 hrs by proteomic analysisDiscovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

Clinical trials (associated diseases)

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

TrialPhaseStatusTitle
NCT06310681Not specifiedCOMPLETEDPilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049Not specifiedNOT_YET_RECRUITINGCognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder