IZUMO1R

Summary

IZUMO1R (IZUMO1 receptor, JUNO, HGNC:32565) is a protein-coding gene on chromosome 11q21, encoding Sperm-egg fusion protein Juno (A6ND01). Receptor for IZUMO1 present at the cell surface of oocytes (oolemma), which is essential for species-specific gamete recognition and fertilization.

Enables signaling receptor activity. Involved in fusion of sperm to egg plasma membrane involved in single fertilization. Located in plasma membrane.

Source: NCBI Gene 390243 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 43 total
• MANE Select transcript: NM_001199206

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:32565
Approved symbol	IZUMO1R
Name	IZUMO1 receptor, JUNO
Location	11q21
Locus type	gene with protein product
Status	Approved
Aliases	Folbp3, JUNO
Ensembl gene	ENSG00000183560
Ensembl biotype	protein_coding
OMIM	615737
Entrez	390243

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000328458, ENST00000440961, ENST00000687084

RefSeq mRNA: 2 — MANE Select: NM_001199206 NM_001199206, NM_001393610

CCDS: CCDS81615

Canonical transcript exons

ENST00000687084 — 5 exons

Exon	Start	End
ENSE00001315423	94306513	94306722
ENSE00001697834	94307165	94307300
ENSE00002206090	94307424	94308146
ENSE00003931306	94305631	94305774
ENSE00003933439	94304580	94304879

Expression profiles

Bgee: expression breadth broad, 54 present calls, max score 53.50.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lymph node	UBERON:0000029	53.50	gold quality
ascending aorta	UBERON:0001496	49.26	gold quality
thoracic aorta	UBERON:0001515	48.48	gold quality
sural nerve	UBERON:0015488	47.92	gold quality
calcaneal tendon	UBERON:0003701	46.77	gold quality
left coronary artery	UBERON:0001626	46.56	gold quality
right coronary artery	UBERON:0001625	45.34	gold quality
smooth muscle tissue	UBERON:0001135	43.98	gold quality
descending thoracic aorta	UBERON:0002345	43.68	gold quality
vermiform appendix	UBERON:0001154	39.60	gold quality
rectum	UBERON:0001052	39.10	gold quality
right ovary	UBERON:0002118	38.98	silver quality
ovary	UBERON:0000992	38.58	gold quality
left adrenal gland cortex	UBERON:0035825	38.31	silver quality
left ovary	UBERON:0002119	38.23	silver quality
muscle tissue	UBERON:0002385	37.96	silver quality
adrenal gland	UBERON:0002369	37.50	gold quality
popliteal artery	UBERON:0002250	37.48	gold quality
tibial artery	UBERON:0007610	37.40	gold quality
gall bladder	UBERON:0002110	37.35	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
right adrenal gland	UBERON:0001233	37.03	gold quality
right atrium auricular region	UBERON:0006631	36.99	gold quality
mucosa of transverse colon	UBERON:0004991	36.82	gold quality
skeletal muscle tissue	UBERON:0001134	36.53	gold quality
tonsil	UBERON:0002372	36.48	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
left adrenal gland	UBERON:0001234	36.30	gold quality
bone marrow cell	CL:0002092	36.16	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 6)

• crystal structures of human IZUMO1, JUNO and the IZUMO1-JUNO complex, establishing the structural basis for the IZUMO1-JUNO-mediated sperm-oocyte interaction (PMID:27309808)
• crystal structures of human IZUMO1 and JUNO in unbound and bound conformations (PMID:27309818)
• JUNO interacts with IZUMO1 during sperm binding. (PMID:27416963)
• Juno single nucleotide polymorphisms associated with fertilization failure and polyspermy after in vitro fertilization in women. (PMID:29243140)
• Study revealed a progressive expression of JUNO according to oocyte maturity and showed that human zona-free oocytes, inseminated in the presence of anti-hJUNO mAb, were not fertilized by human sperm. (PMID:30517645)
• Genetic diversity in the IZUMO1-JUNO protein-receptor pair involved in human reproduction. (PMID:34879103)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	folr	ENSDARG00000102442
mus_musculus	Izumo1r	ENSMUSG00000031933
rattus_norvegicus	Izumo1r	ENSRNOG00000019894

Paralogs (4): FOLR1 (ENSG00000110195), FOLR3 (ENSG00000110203), RTBDN (ENSG00000132026), FOLR2 (ENSG00000165457)

Protein

Protein identifiers

Sperm-egg fusion protein Juno — A6ND01 (reviewed: A6ND01)

Alternative names: Folate receptor 4, Folate receptor delta, IZUMO1 receptor protein JUNO

All UniProt accessions (1): A6ND01

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for IZUMO1 present at the cell surface of oocytes (oolemma), which is essential for species-specific gamete recognition and fertilization. The IZUMO1:IZUMO1R/JUNO interaction is a necessary adhesion event between sperm and egg that is required for fertilization but is not sufficient for cell fusion. The ligand-receptor interaction probably does not act as a membrane ‘fusogen’. Does not bind folate.

Subunit / interactions. Monomer. Interacts with IZUMO1; the interaction is direct. IZUMO1 and IZUMO1R/JUNO form a complex with 1:1 stoichiometry. Interacts with FCRL3/MAIA; FCRL3/MAIA replaces IZUMO1R/JUNO as IZUMO1 receptor after sperm-egg adhesion, thereby permitting species-specific gamete fusion. Interacts with WDR54.

Subcellular location. Cell membrane. Cell projection. Microvillus membrane.

Tissue specificity. Expressed in unfertilized oocytes (at protein level).

Post-translational modifications. The protein is rapidly cleaved following fertilization, being only weakly detectable in zona-intact fertilized eggs at telophase II and undetectable at the pronuclear stage. Sheding is probably required to block to polyspermy and ensuring egg fusion with a single sperm.

Miscellaneous. Gene prediction based on similarity to orthologs.

Similarity. Belongs to the folate receptor family.

Isoforms (2)

UniProt ID	Names	Canonical?
A6ND01-1	1	yes
A6ND01-2	2

RefSeq proteins (2): NP_001186135, NP_001380539 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004269	Folate_rcpt	Family
IPR018143	Folate_rcpt-like	Domain

Pfam: PF03024

UniProt features (44 total): strand 11, helix 10, disulfide bond 8, mutagenesis site 5, turn 3, signal peptide 1, chain 1, splice variant 1, propeptide 1, region of interest 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5F4Q	X-RAY DIFFRACTION	1.8
5JKA	X-RAY DIFFRACTION	2
5F4E	X-RAY DIFFRACTION	2.4
5JKE	X-RAY DIFFRACTION	2.86
5JKC	X-RAY DIFFRACTION	2.9
5JKD	X-RAY DIFFRACTION	2.9
5JKB	X-RAY DIFFRACTION	3.23

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6ND01-F1	87.38	0.75

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 (1): 228

Disulfide bonds (8): 86–143, 132–206, 136–186, 149–166, 27–55, 47–95, 56–99, 79–172

Glycosylation sites (1): 73

Mutagenesis-validated functional residues (5):

Position	Phenotype
45	nearly abolishes interaction with izumo1.
45	abolishes interaction with izumo1.
62	nearly abolishes interaction with izumo1.
81	abolishes interaction with izumo1.
163	mildly decreases interaction with izumo1.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 113 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOCC_CELL_SURFACE, GOBP_SPERM_EGG_RECOGNITION, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_PLASMA_MEMBRANE_FUSION, GOBP_MEMBRANE_ORGANIZATION, GOBP_FERTILIZATION, GOBP_CELL_CELL_RECOGNITION, GOMF_SIGNALING_RECEPTOR_BINDING, GOCC_CELL_PROJECTION_MEMBRANE, GOCC_MICROVILLUS, GOCC_MICROVILLUS_MEMBRANE

GO Biological Process (4): cell adhesion (GO:0007155), single fertilization (GO:0007338), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), sperm-egg recognition (GO:0035036)

GO Molecular Function (3): signaling receptor binding (GO:0005102), signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), microvillus membrane (GO:0031528), membrane (GO:0016020), cell projection (GO:0042995), side of membrane (GO:0098552)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
single fertilization	2
membrane	2
cellular process	1
fertilization	1
cellular process involved in reproduction in multicellular organism	1
cell-cell recognition	1
protein binding	1
molecular transducer activity	1
binding	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
microvillus	1
cell projection membrane	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

702 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IZUMO1R	IZUMO1	Q8IYV9	995
IZUMO1R	FOLH1	Q04609	790
IZUMO1R	EGFR	P00533	681
IZUMO1R	TFRC	P02786	678
IZUMO1R	ERBB2	P04626	638
IZUMO1R	SLC46A1	Q96NT5	588
IZUMO1R	SPACA6	W5XKT8	585
IZUMO1R	EPCAM	P16422	547
IZUMO1R	MUC1	P13931	533
IZUMO1R	TMEM95	Q3KNT9	525
IZUMO1R	MSLN	Q13421	505
IZUMO1R	CD9	P21926	503
IZUMO1R	ALB	P02768	482
IZUMO1R	SLC19A1	P41440	454
IZUMO1R	FCGR3B	O75015	449
IZUMO1R	DHFR	P00374	449

IntAct

2 interactions, top by confidence:

A	B	Type	Score
DYNC2LI1	IZUMO1R	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A3Q1LRJ2, A6ND01, B8JI67, E1B9E5, F1M928, O15547, P02702, P02752, P0DJF3, P0DN42, P10820, P14207, P15328, P16229, P27767, P35846, P41439, P48251, P51653, P86009, Q05685, Q3HRV3, Q3S2X5, Q3UPR9, Q3V5L5, Q4TUC0, Q5EA85, Q5FB95, Q5M936, Q62178, Q62190, Q64663, Q64716, Q6DFV8, Q765H6, Q7TPG6, Q7Z5A8, Q8BMN4, Q8IVN8, Q8N2E2

Diamond homologs: A6ND01, F1M928, P02702, P02752, P14207, P15328, P35846, P41439, P86009, Q05685, Q9EQF4, Q5DRQ5, P85896

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

501 predictions. Top by Δscore:

Variant	Effect	Δscore
11:94305771:GGAG:G	donor_gain	1.0000
11:94305772:G:GT	donor_gain	1.0000
11:94305772:GAGG:G	donor_loss	1.0000
11:94305773:AG:A	donor_loss	1.0000
11:94305774:GGT:G	donor_loss	1.0000
11:94305775:G:GA	donor_loss	1.0000
11:94306651:GC:G	donor_gain	1.0000
11:94306706:G:GT	donor_gain	1.0000
11:94306635:G:GT	donor_gain	0.9900
11:94306664:A:AG	donor_gain	0.9900
11:94306664:A:G	donor_gain	0.9900
11:94306706:G:T	donor_gain	0.9900
11:94305772:G:T	donor_gain	0.9800
11:94306698:GCCA:G	donor_gain	0.9800
11:94306701:A:AG	donor_gain	0.9700
11:94306702:G:GG	donor_gain	0.9700
11:94306717:TGGG:T	donor_gain	0.9600
11:94305739:A:T	donor_gain	0.9500
11:94306573:G:GT	donor_gain	0.9500
11:94307299:GG:G	donor_gain	0.9500
11:94307300:GG:G	donor_gain	0.9500
11:94306511:A:AG	acceptor_gain	0.9400
11:94306512:G:GG	acceptor_gain	0.9400
11:94307480:A:AG	acceptor_gain	0.9400
11:94305773:A:T	donor_gain	0.9300
11:94307485:A:AG	acceptor_gain	0.9300
11:94307486:G:GG	acceptor_gain	0.9300
11:94306512:GTGC:G	acceptor_gain	0.9200
11:94306652:C:G	donor_gain	0.9200
11:94306652:C:T	donor_gain	0.9200

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008389 (11:94307016 G>A), RS1000679709 (11:94307836 C>A), RS1000682192 (11:94305978 G>A), RS1001134329 (11:94307396 T>G), RS1001220646 (11:94305769 G>A), RS1001415843 (11:94305841 C>A,T), RS1002138360 (11:94306198 G>T), RS1002398356 (11:94306472 C>A,G,T), RS1002455873 (11:94308629 A>C), RS1002634048 (11:94303583 T>C), RS1007271828 (11:94302641 C>T), RS1007448065 (11:94308313 G>A,C), RS1007895106 (11:94305177 A>C,G), RS1008147495 (11:94304483 T>C), RS1008281100 (11:94305504 G>C)

Disease associations

OMIM: gene MIM:615737 | 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
GCST011352_40	Alanine aminotransferase levels	1.000000e-24

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Lactic Acid	increases expression	1

Clinical trials (associated diseases)

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