IZUMO1

Summary

IZUMO1 (izumo sperm-oocyte fusion 1, HGNC:28539) is a protein-coding gene on chromosome 19q13.33, encoding Izumo sperm-egg fusion protein 1 (Q8IYV9). Essential sperm cell-surface protein required for fertilization by acting as a ligand for IZUMO1R/JUNO receptor on egg.

The sperm-specific protein Izumo, named for a Japanese shrine dedicated to marriage, is essential for sperm-egg plasma membrane binding and fusion (Inoue et al., 2005 [PubMed 15759005]).

Source: NCBI Gene 284359 — RefSeq curated summary.

At a glance

• GWAS associations: 27
• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_182575

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28539
Approved symbol	IZUMO1
Name	izumo sperm-oocyte fusion 1
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	IZUMO, MGC34799, OBF
Ensembl gene	ENSG00000182264
Ensembl biotype	protein_coding
OMIM	609278
Entrez	284359

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 2 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000332955, ENST00000595517, ENST00000595937, ENST00000597553, ENST00000599871, ENST00000602105

RefSeq mRNA: 3 — MANE Select: NM_182575 NM_001321864, NM_001321865, NM_182575

CCDS: CCDS12732

Canonical transcript exons

ENST00000332955 — 10 exons

Exon	Start	End
ENSE00001309030	48746435	48746909
ENSE00001327054	48745625	48745932
ENSE00002264459	48740852	48741028
ENSE00003548952	48744453	48744539
ENSE00003553011	48745214	48745288
ENSE00003587766	48741789	48741942
ENSE00003595181	48744175	48744195
ENSE00003630824	48743445	48743525
ENSE00003662208	48741301	48741478
ENSE00003666989	48742209	48742309

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 89.65.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	89.65	gold quality
left testis	UBERON:0004533	89.63	gold quality
sperm	CL:0000019	86.81	gold quality
testis	UBERON:0000473	86.06	gold quality
body of pancreas	UBERON:0001150	84.45	gold quality
upper lobe of left lung	UBERON:0008952	77.02	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.39	gold quality
body of stomach	UBERON:0001161	76.14	gold quality
cerebellar hemisphere	UBERON:0002245	76.04	gold quality
cerebellar cortex	UBERON:0002129	75.81	gold quality
upper lobe of lung	UBERON:0008948	74.83	gold quality
cerebellum	UBERON:0002037	73.30	gold quality
right adrenal gland cortex	UBERON:0035827	73.28	gold quality
right lung	UBERON:0002167	73.18	gold quality
right adrenal gland	UBERON:0001233	72.54	gold quality
stomach	UBERON:0000945	71.92	gold quality
pancreas	UBERON:0001264	71.85	gold quality
apex of heart	UBERON:0002098	69.36	gold quality
spleen	UBERON:0002106	68.51	gold quality
left adrenal gland cortex	UBERON:0035825	68.36	gold quality
left adrenal gland	UBERON:0001234	68.34	gold quality
adrenal cortex	UBERON:0001235	67.36	gold quality
omental fat pad	UBERON:0010414	66.85	gold quality
peritoneum	UBERON:0002358	66.78	gold quality
adrenal gland	UBERON:0002369	66.26	gold quality
lower esophagus mucosa	UBERON:0035834	65.80	gold quality
adipose tissue of abdominal region	UBERON:0007808	65.42	gold quality
left uterine tube	UBERON:0001303	65.15	gold quality
heart left ventricle	UBERON:0002084	65.11	gold quality
cardiac ventricle	UBERON:0002082	64.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.52

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 7)

• human sperm contain Izumo and addition of the antibody against human Izumo left the sperm unable to fuse with zona-free hamster eggs [Izumo] (PMID:15759005)
• We observed in our populations two combinations of four polymorphisms that appeared to be preferentially linked (CGG-CG and TAA-TT) without any significant difference between different genotype repartitions. (PMID:18082733)
• these findings indicate that human sperm expresses Izumo protein, and the immunoinfertile female sera have circulating isoantibodies against this protein. (PMID:23279005)
• 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)
• Genetic diversity in the IZUMO1-JUNO protein-receptor pair involved in human reproduction. (PMID:34879103)
• No evidence for a direct extracellular interaction between human Fc receptor-like 3 (MAIA) and the sperm ligand IZUMO1. (PMID:38381819)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Izumo1	ENSMUSG00000064158
rattus_norvegicus		ENSRNOG00000089371

Protein

Protein identifiers

Izumo sperm-egg fusion protein 1 — Q8IYV9 (reviewed: Q8IYV9)

Alternative names: Oocyte binding/fusion factor, Sperm-specific protein izumo

All UniProt accessions (2): Q8IYV9, M0R0B8

UniProt curated annotations — full annotation on UniProt →

Function. Essential sperm cell-surface protein required for fertilization by acting as a ligand for IZUMO1R/JUNO receptor on egg. 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’. Acts a ligand for the human-specific oolemma epitope FCRL3/MAIA during fertilization. FCRL3/MAIA replaces IZUMO1R/JUNO as IZUMO1 receptor after sperm-egg adhesion, which permits species-specific gamete fusion. Plays a critical role in sperm-oolemma binding prior to plasma membrane fusion. Can mediate cell-cell fusion in cultured mammalian cells independently of its binding to IZUMO1R/JUNO.

Subunit / interactions. Monomer, homodimer; disulfide-linked and homooligomer; depending on the context. Interacts with IZUMO1R/JUNO. IZUMO1 and IZUMO1R/JUNO form a complex with 1:1 stoichiometry. In gamete recognition, IZUMO1R/JUNO first binds to monomeric IZUMO1. The weak, but specific interaction with IZUMO1R/JUNO induces IZUMO1 homodimerization. The process follows a tight binding phase where IZUMO1 bends the entire structure towards the sperm membrane side through a thiol-disulfide exchange reaction. The molecule no longer binds to IZUMO1R/JUNO and instead binds to a putative second oocyte receptor. Interacts with ACE3. Part of a oolemmal binding multimeric complex (IZUMO1 complex) composed at least of IZUMO1 and GLIPR1L1; the complex assemblage is influenced by the maturation status of the male germ cell. Interacts with GLIPR1L1. Interacts with FREY; the interaction retains IZUMO1 at the endoplasmic reticulum membrane and coordinates IZUMO1 complex assembly. Interacts with FCRL3/MAIA (via extracellular domain); the interaction replaces IZUMO1R/JUNO as IZUMO1 receptor after sperm-egg adhesion. Interacts with WDR54. Forms a complex with SPACA6 and TMEM81 on spermatocyte cell membrane.

Subcellular location. Cell membrane. Cytoplasmic vesicle. Secretory vesicle. Acrosome membrane.

Tissue specificity. Sperm-specific (at protein level). Detectable on sperm surface only after the acrosome reaction.

Post-translational modifications. N-glycosylated. Glycosylation is not essential for fusion and for proper protein trafficking in sperm. Phosphorylated. The cytoplasmic C-terminus is phosphorylated and undergoes phosphorylation changes during epididymal transit.

Domain organisation. The extracellular domain assumes a distinct boomerang shape when not bound to IZUMO1R/JUNO. Interaction with IZUMO1R/JUNO triggers a conformation change, so that the IZUMO1 extracellular domain assumes an upright conformation. The cytoplasmic C-terminus region is not essential for fertilization. It is however required for protein stability.

Miscellaneous. Izumo is the name of a Japanese shrine to marriage.

Similarity. Belongs to the Izumo family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IYV9-1	1	yes
Q8IYV9-2	2
Q8IYV9-3	3

RefSeq proteins (3): NP_001308793, NP_001308794, NP_872381* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013783	Ig-like_fold	Homologous_superfamily
IPR029389	IZUMO	Family
IPR032699	Izumo-Ig	Domain
IPR032700	IZUMO1	Family
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF15005, PF16706

UniProt features (49 total): strand 13, helix 10, disulfide bond 5, splice variant 4, mutagenesis site 4, topological domain 2, turn 2, signal peptide 1, chain 1, sequence variant 1, sequence conflict 1, transmembrane region 1, domain 1, region of interest 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5JK9	X-RAY DIFFRACTION	2.1
5F4E	X-RAY DIFFRACTION	2.4
5JKE	X-RAY DIFFRACTION	2.86
5F4V	X-RAY DIFFRACTION	2.9
5JKC	X-RAY DIFFRACTION	2.9
5JKD	X-RAY DIFFRACTION	2.9
5F4T	X-RAY DIFFRACTION	3.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IYV9-F1	81.86	0.61

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): 325

Disulfide bonds (5): 25–152, 135–159, 139–165, 182–233, 22–149

Glycosylation sites (1): 204

Mutagenesis-validated functional residues (4):

Position	Phenotype
71	mildly decreases interaction with izumo1r.
148	abolishes interaction with izumo1r.
157	nearly abolishes interaction with izumo1r.
160	nearly abolishes interaction with izumo1r.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1300645	Acrosome Reaction and Sperm:Oocyte Membrane Binding
R-HSA-1187000	Fertilization
R-HSA-1474165	Reproduction

MSigDB gene sets: 77 (showing top): GOBP_SINGLE_FERTILIZATION, GOCC_SECRETORY_GRANULE, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_CELL_CELL_ADHESION, 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, GOBP_BINDING_OF_SPERM_TO_ZONA_PELLUCIDA, GOBP_SYNCYTIUM_FORMATION

GO Biological Process (8): syncytium formation by cell-cell fusion (GO:0000768), cell adhesion (GO:0007155), binding of sperm to zona pellucida (GO:0007339), fusion of sperm to egg plasma membrane involved in single fertilization (GO:0007342), sperm-egg recognition (GO:0035036), signal transduction (GO:0007165), single fertilization (GO:0007338), heterotypic cell-cell adhesion (GO:0034113)

GO Molecular Function (6): signaling receptor binding (GO:0005102), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding involved in heterotypic cell-cell adhesion (GO:0086080), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

GO Cellular Component (7): acrosomal vesicle (GO:0001669), acrosomal membrane (GO:0002080), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), protein complex involved in cell-cell adhesion (GO:0098635), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Fertilization	1
Reproduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
single fertilization	2
protein binding	2
cell-cell fusion	1
sperm-egg recognition	1
cellular process involved in reproduction in multicellular organism	1
cell-cell recognition	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
fertilization	1
cell-cell adhesion	1
identical protein binding	1
protein dimerization activity	1
heterotypic cell-cell adhesion	1
cell-cell adhesion mediator activity	1
binding	1
signaling receptor binding	1
signal transduction	1
signaling receptor activator activity	1
secretory granule	1
acrosomal vesicle	1
secretory granule membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
protein complex involved in cell adhesion	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IZUMO1	IZUMO1R	A6ND01	995
IZUMO1	TMEM95	Q3KNT9	873
IZUMO1	IZUMO4	Q1ZYL8	819
IZUMO1	SPACA6	W5XKT8	812
IZUMO1	SPACA1	Q9HBV2	794
IZUMO1	CD9	P21926	765
IZUMO1	ZP3	P21754	754
IZUMO1	IZUMO3	Q5VZ72	746
IZUMO1	IZUMO2	Q6UXV1	726
IZUMO1	TSSK6	Q9BXA6	659
IZUMO1	ZP1	P60852	647
IZUMO1	ZP2	Q05996	644
IZUMO1	ADAM2	P78326	617
IZUMO1	DCST2	Q5T1A1	613
IZUMO1	FOLR1	P15328	610

IntAct

6 interactions, top by confidence:

A	B	Type	Score
IZUMO1	ADCY3	psi-mi:“MI:0914”(association)	0.530
IZUMO1	LILRA5	psi-mi:“MI:0915”(physical association)	0.400
IZUMO1	CNOT1	psi-mi:“MI:0914”(association)	0.350
IZUMO1	PTPRF	psi-mi:“MI:0914”(association)	0.350
IZUMO1	HMOX2	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): SLC39A11 (Affinity Capture-MS), CRACR2A (Affinity Capture-MS), FAM84B (Affinity Capture-MS), CDC16 (Affinity Capture-MS), GHITM (Affinity Capture-MS), ACVR2B (Affinity Capture-MS), ANKRD13D (Affinity Capture-MS), SLC4A7 (Affinity Capture-MS), LPGAT1 (Affinity Capture-MS), PTPRD (Affinity Capture-MS), CDC26 (Affinity Capture-MS), CNOT11 (Affinity Capture-MS), ANKRD13A (Affinity Capture-MS), RQCD1 (Affinity Capture-MS), ADCY3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GUA7, A0A3Q1LRJ2, A2T6Z6, E9Q8Q8, O46673, O77049, O88823, P01588, P07865, P22301, P29676, P43480, P46651, P48411, P51496, P51497, P51746, P55029, P79338, Q0Z972, Q25BC1, Q28374, Q28C41, Q2PE73, Q3KNT9, Q4VK74, Q5Q0V6, Q5ZJY9, Q6A2H4, Q6AY06, Q6H8S9, Q6H8T0, Q6H8T1, Q6H8T2, Q6UXV1, Q865X4, Q8BGT0, Q8CGK6, Q8CJ70, Q8IU54

Diamond homologs: Q6AY06, Q8IYV9, Q9D9J7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1691 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48741299:A:AC	donor_gain	1.0000
19:48741300:C:CC	donor_gain	1.0000
19:48741300:CG:C	donor_gain	1.0000
19:48741364:G:A	donor_gain	1.0000
19:48741474:CAACA:C	acceptor_gain	1.0000
19:48741475:AACA:A	acceptor_gain	1.0000
19:48741477:CA:C	acceptor_gain	1.0000
19:48741479:C:CC	acceptor_gain	1.0000
19:48745645:T:TA	donor_gain	1.0000
19:48741262:A:AC	donor_gain	0.9900
19:48741263:C:CC	donor_gain	0.9900
19:48741295:GCTT:G	donor_loss	0.9900
19:48741296:CTTAC:C	donor_loss	0.9900
19:48741299:ACGC:A	donor_loss	0.9900
19:48741300:CGCAA:C	donor_gain	0.9900
19:48741476:ACA:A	acceptor_gain	0.9900
19:48741477:CAC:C	acceptor_gain	0.9900
19:48741478:AC:A	acceptor_loss	0.9900
19:48741479:C:CG	acceptor_loss	0.9900
19:48741482:T:C	acceptor_gain	0.9900
19:48741482:T:TC	acceptor_gain	0.9900
19:48744452:CCCT:C	donor_gain	0.9900
19:48745663:T:A	donor_gain	0.9900
19:48741294:TGCT:T	donor_loss	0.9800
19:48741300:CGCA:C	donor_gain	0.9800
19:48741784:CTGA:C	donor_loss	0.9800
19:48741785:TGACC:T	donor_loss	0.9800
19:48741786:GA:G	donor_loss	0.9800
19:48741788:C:CA	donor_loss	0.9800
19:48744451:AC:A	donor_gain	0.9800

AlphaMissense

2301 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:48742251:C:A	W186C	1.000
19:48742251:C:G	W186C	1.000
19:48742253:A:G	W186R	0.999
19:48742253:A:T	W186R	0.999
19:48741845:C:G	C233S	0.996
19:48741846:A:T	C233S	0.996
19:48742215:A:C	F198L	0.996
19:48742215:A:T	F198L	0.996
19:48742217:A:G	F198L	0.996
19:48741848:C:G	R232P	0.995
19:48742264:C:T	C182Y	0.995
19:48744463:G:C	F129L	0.995
19:48744463:G:T	F129L	0.995
19:48744465:A:G	F129L	0.995
19:48741846:A:G	C233R	0.994
19:48742216:A:C	F198C	0.994
19:48742264:C:G	C182S	0.994
19:48742265:A:T	C182S	0.994
19:48744175:C:A	G140C	0.994
19:48744464:A:C	F129C	0.994
19:48741799:A:C	F248L	0.993
19:48741799:A:T	F248L	0.993
19:48741801:A:G	F248L	0.993
19:48741845:C:T	C233Y	0.993
19:48742216:A:G	F198S	0.993
19:48742265:A:G	C182R	0.993
19:48743468:C:G	C159S	0.993
19:48743469:A:T	C159S	0.993
19:48744189:C:G	C135S	0.993
19:48744190:A:T	C135S	0.993

dbSNP variants (sampled 300 via entrez): RS1000099034 (19:48748486 T>A,C), RS1000154500 (19:48742383 T>G), RS1000302332 (19:48748251 G>A), RS1000330236 (19:48748481 C>T), RS1001275986 (19:48740742 T>G), RS1001495075 (19:48747495 C>G,T), RS1001832771 (19:48747916 C>A), RS1001934255 (19:48747940 ACACACACACACACAAACC>A), RS1002114990 (19:48745833 A>T), RS1002183027 (19:48747149 A>G), RS1002210285 (19:48742301 C>T), RS1002283866 (19:48741962 G>C,T), RS1002603134 (19:48740441 C>T), RS1003571267 (19:48746223 A>C), RS1003583501 (19:48744122 G>A,C)

Disease associations

OMIM: gene MIM:609278 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST000847_1	Retinal vascular caliber	2.000000e-25
GCST001241_6	Bipolar disorder	3.000000e-06
GCST001729_25	Crohn’s disease	1.000000e-15
GCST001844_2	Dietary macronutrient intake	8.000000e-09
GCST003372_5	Glomerular filtration rate (creatinine)	1.000000e-06
GCST004131_128	Inflammatory bowel disease	5.000000e-06
GCST004132_59	Crohn’s disease	4.000000e-11
GCST006716_15	Alcohol use disorder (total score)	3.000000e-08
GCST007483_53	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5.000000e-08
GCST007487_46	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-08
GCST007500_38	Waist-to-hip ratio adjusted for BMI (additive genetic model)	6.000000e-08
GCST007502_36	Waist-to-hip ratio adjusted for BMI (additive genetic model)	4.000000e-08
GCST008062_47	Blood urea nitrogen levels	4.000000e-24
GCST008757_4	Alcohol consumption	3.000000e-15
GCST008811_46	Alcohol consumption (drinks per week)	9.000000e-12
GCST010132_5	Processed meat consumption	2.000000e-11
GCST010134_4	Non-oily fish consumption	3.000000e-16
GCST010135_4	Oily fish consumption	2.000000e-16
GCST010136_42	Fruit consumption	3.000000e-10
GCST010137_4	Cooked vegetable consumption	3.000000e-09
GCST010140_48	Pork consumption	2.000000e-16
GCST010142_1	Fish- and plant-related diet	7.000000e-13
GCST010142_45	Fish- and plant-related diet	3.000000e-08
GCST010142_68	Fish- and plant-related diet	6.000000e-10
GCST010143_10	Meat-related diet	4.000000e-09
GCST010143_20	Meat-related diet	8.000000e-12
GCST90002397_436	Mean spheric corpuscular volume	6.000000e-19

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004731	eye measurement
EFO:0003939	energy intake
EFO:0009458	alcohol use disorder measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008111	diet measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases expression	2
terbufos	increases methylation	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Fonofos	increases methylation	1
Parathion	increases methylation	1

Clinical trials (associated diseases)

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