SPAM1

Summary

SPAM1 (sperm adhesion molecule 1, HGNC:11217) is a protein-coding gene on chromosome 7q31.32, encoding Hyaluronidase PH-20 (P38567). Involved in sperm-egg adhesion.

Hyaluronidase degrades hyaluronic acid, a major structural proteoglycan found in extracellular matrices and basement membranes. Six members of the hyaluronidase family are clustered into two tightly linked groups on chromosome 3p21.3 and 7q31.3. This gene was previously referred to as HYAL1 and HYA1 and has since been assigned the official symbol SPAM1; another family member on chromosome 3p21.3 has been assigned HYAL1. This gene encodes a GPI-anchored enzyme located on the human sperm surface and inner acrosomal membrane. This multifunctional protein is a hyaluronidase that enables sperm to penetrate through the hyaluronic acid-rich cumulus cell layer surrounding the oocyte, a receptor that plays a role in hyaluronic acid induced cell signaling, and a receptor that is involved in sperm-zona pellucida adhesion. Abnormal expression of this gene in tumors has implicated this protein in degradation of basement membranes leading to tumor invasion and metastasis. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6677 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 67 total
• MANE Select transcript: NM_153189

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11217
Approved symbol	SPAM1
Name	sperm adhesion molecule 1
Location	7q31.32
Locus type	gene with protein product
Status	Approved
Aliases	HYAL5, PH-20, SPAG15
Ensembl gene	ENSG00000106304
Ensembl biotype	protein_coding
OMIM	600930
Entrez	6677

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000223028, ENST00000340011, ENST00000402183, ENST00000413927, ENST00000439500, ENST00000460182, ENST00000682466

RefSeq mRNA: 5 — MANE Select: NM_153189 NM_001174044, NM_001174045, NM_001174046, NM_003117, NM_153189

CCDS: CCDS5790, CCDS5791

Canonical transcript exons

ENST00000682466 — 5 exons

Exon	Start	End
ENSE00000720001	123954997	123955086
ENSE00000882058	123953365	123954524
ENSE00001188436	123959484	123960046
ENSE00001478700	123949872	123949983
ENSE00003921096	123925241	123925352

Expression profiles

Bgee: expression breadth broad, 31 present calls, max score 96.37.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0089 / max 5.4130, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80863	0.0089	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	96.37	gold quality
male germ cell	CL:0000015	93.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.40	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.72	gold quality
left testis	UBERON:0004533	75.20	gold quality
right testis	UBERON:0004534	74.20	gold quality
testis	UBERON:0000473	73.79	gold quality
olfactory bulb	UBERON:0002264	67.30	gold quality
tibialis anterior	UBERON:0001385	65.22	silver quality
diaphragm	UBERON:0001103	64.22	gold quality
buccal mucosa cell	CL:0002336	62.92	gold quality
adult organism	UBERON:0007023	58.64	silver quality
deltoid	UBERON:0001476	58.40	gold quality
ileal mucosa	UBERON:0000331	56.01	silver quality
quadriceps femoris	UBERON:0001377	55.55	gold quality
cranial nerve II	UBERON:0000941	55.24	silver quality
vastus lateralis	UBERON:0001379	54.76	gold quality
skin of hip	UBERON:0001554	53.04	silver quality
triceps brachii	UBERON:0001509	52.70	gold quality
pancreatic ductal cell	CL:0002079	52.69	silver quality
epithelial cell of pancreas	CL:0000083	49.93	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.75	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
muscle organ	UBERON:0001630	48.91	gold quality
thymus	UBERON:0002370	48.90	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.92

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 9)

• SPAM1 mRNA & protein occur in all 3 regions of epididymis & vas deferens. It has hyaluronidase activity at pH 7.0. The proximal promoter has epididymal transcription factor sites including androgen receptor elements. Its role may be in sperm maturation. (PMID:12932297)
• The interaction between SPAM1, ARSA and HSPA2 in a multimeric complex mediating sperm-egg interaction. (PMID:23209833)
• HSPA2 regulates the expression of sperm surface receptors involved in human sperm-oocyte recognition, such as arylsulfatase A and SPAM1. (PMID:23247813)
• PH20 is elevated in demyelinating lesions and that increased PH20 expression is sufficient to inhibit oligodendrocyte precursor cell maturation and remyelination. (PMID:23463525)
• results indicate that neither rHuPH20 nor its directly generated HA catabolites have inflammatory properties in the air pouch model, and rHuPH20 can instead inhibit some aspects of inflammation, such as neutrophil infiltration into the air pouch. (PMID:24778442)
• Human posterior head 20 (hPH20) and homo sapiens sperm acrosome associated 1 (hSPACA1) immunocontraceptive epitopes reduced fertility in male/female mice. (PMID:25209425)
• Human Hyaluronidase PH20 Potentiates the Antitumor Activities of Mesothelin-Specific CAR-T Cells Against Gastric Cancer. (PMID:34326835)
• N-Glycosylation and enzymatic activity of the rHuPH20 expressed in Chinese hamster ovary cells. (PMID:34520755)
• Low acrosin activity is associated with decreased Spam1/acrosin expression and GSH deficiency-caused premature acrosome release of human sperm cells. (PMID:37833433)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	spam1	ENSDARG00000004199
mus_musculus	Hyal5	ENSMUSG00000029678
mus_musculus	Spam1	ENSMUSG00000029682
rattus_norvegicus	Spam1	ENSRNOG00000007231
rattus_norvegicus	Hyal5	ENSRNOG00000039466
caenorhabditis_elegans		WBGENE00011923

Paralogs (4): HYAL2 (ENSG00000068001), HYAL4 (ENSG00000106302), HYAL1 (ENSG00000114378), HYAL3 (ENSG00000186792)

Protein

Protein identifiers

Hyaluronidase PH-20 — P38567 (reviewed: P38567)

Alternative names: Hyaluronoglucosaminidase PH-20, Sperm adhesion molecule 1, Sperm surface protein PH-20

All UniProt accessions (3): P38567, C9J2X5, Q5D1J4

UniProt curated annotations — full annotation on UniProt →

Function. Involved in sperm-egg adhesion. Upon fertilization sperm must first penetrate a layer of cumulus cells that surrounds the egg before reaching the zona pellucida. The cumulus cells are embedded in a matrix containing hyaluronic acid which is formed prior to ovulation. This protein aids in penetrating the layer of cumulus cells by digesting hyaluronic acid.

Subcellular location. Cell membrane.

Tissue specificity. Testis.

Post-translational modifications. N-glycosylated.

Similarity. Belongs to the glycosyl hydrolase 56 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P38567-1	1	yes
P38567-2	2

RefSeq proteins (5): NP_001167515, NP_001167516, NP_001167517, NP_003108, NP_694859* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001439	Hyaluronidase_PH20/Hyal5	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR018155	Hyaluronidase	Family

Pfam: PF01630

Enzyme classification (BRENDA):

• EC 3.2.1.35 — hyaluronoglucosaminidase (BRENDA: 70 organisms, 156 substrates, 263 inhibitors, 27 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HYALURONAN	0.038–0.367	11
CHONDROITIN	0.12	1
CHONDROITIN SULFATE	0.48	1
CHONDROITIN SULFATE A	0.66	1
CHONDROITIN SULFATE C	2.16	1
CHONDROITIN SULFATE D	0.5	1
HYALURONIC ACID	0.0009	1
HYALURONIC ACID FROM STREPTOCOCCUS PYOGENES (35	49.3	1

UniProt features (60 total): strand 19, helix 12, glycosylation site 6, disulfide bond 5, mutagenesis site 5, turn 3, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, splice variant 1, propeptide 1, active site 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9JUB	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P38567-F1	88.42	0.78

Antibody-complex structures (SAbDab): 1 — 9JUB

Functional residue map

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

Catalytic / active sites (1): 148 (proton donor)

Post-translational modifications (1): 490

Disulfide bonds (5): 60–351, 224–238, 376–387, 381–435, 437–464

Glycosylation sites (6): 393, 82, 166, 235, 254, 368

Mutagenesis-validated functional residues (5):

Position	Phenotype
146	reduces activity by 80%.
148	loss of activity.
211	reduces activity by over 90%.
284	loss of activity.
287	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2160916	Hyaluronan degradation
R-HSA-2534343	Interaction With Cumulus Cells And The Zona Pellucida

MSigDB gene sets: 99 (showing top): GOBP_SINGLE_FERTILIZATION, GOCC_SECRETORY_GRANULE, GOBP_MEMBRANE_FUSION, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_HYALURONAN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_HYALURONAN_METABOLIC_PROCESS, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_SPERM_EGG_RECOGNITION, GOBP_AMINOGLYCAN_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION

GO Biological Process (6): carbohydrate metabolic process (GO:0005975), 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), hyaluronan catabolic process (GO:0030214), single fertilization (GO:0007338)

GO Molecular Function (3): hyalurononglucosaminidase activity (GO:0004415), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (4): acrosomal vesicle (GO:0001669), plasma membrane (GO:0005886), side of membrane (GO:0098552), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Hyaluronan metabolism	1
Fertilization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane	2
cellular anatomical structure	2
primary metabolic process	1
cellular process	1
sperm-egg recognition	1
single fertilization	1
cellular process involved in reproduction in multicellular organism	1
glycosaminoglycan catabolic process	1
hyaluronan metabolic process	1
fertilization	1
hexosaminidase activity	1
catalytic activity	1
hydrolase activity	1
secretory granule	1
cell periphery	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

2203 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAM1	SPAG9	O60271	886
SPAM1	HAS2	Q92819	784
SPAM1	HSPA2	P54652	754
SPAM1	MST1R	Q04912	742
SPAM1	CD44	P16070	727
SPAM1	HAS3	O00219	644
SPAM1	HAS1	Q92839	636
SPAM1	CEMIP	Q8WUJ3	622
SPAM1	ZAN	Q9Y493	606
SPAM1	ARSA	P15289	603
SPAM1	HMMR	O75330	601
SPAM1	ZP3	P21754	593
SPAM1	ADAM2	P78326	583
SPAM1	SPACA1	Q9HBV2	571
SPAM1	SPESP1	Q6UW49	547

IntAct

4 interactions, top by confidence:

A	B	Type	Score
	SPAM1	psi-mi:“MI:0194”(cleavage reaction)	0.440

BioGRID (2): SPAM1 (Affinity Capture-MS), SPAM1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B5GR44, A0A0D3QS97, A1L314, A4IH88, A7MCS3, B9DFR3, E7F0Z8, F4I107, F4I839, O35298, O54728, O80731, P38566, P38567, P38568, P70683, Q03311, Q0P6H9, Q3TTY0, Q3UUQ7, Q3V5L5, Q4V398, Q5GF25, Q5RBP9, Q60963, Q66GM8, Q6DBP4, Q6E279, Q6NQ51, Q75T13, Q765A7, Q765H6, Q812F3, Q84JS1, Q84WF0, Q8BG22, Q8BXJ9, Q8N2E2, Q93ZR8, Q940J8

Diamond homologs: A3QVN2, A3QVN3, A3QVN4, A3QVN5, A3QVN6, A3QVN9, A3QVP0, B3EWP2, C0HLL4, C0HLL5, E0XKJ9, G5ECE8, I0CME8, J3S820, O35632, O43820, P23613, P38566, P38567, P38568, P48794, P49370, P49371, P85841, P86100, P86687, P86875, Q05A56, Q08169, Q12794, Q12891, Q2M3T9, Q5D7H4, Q5E985, Q5REQ1, Q62803, Q6RHW2, Q6RHW4, Q76HM9, Q76HN1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

906 predictions. Top by Δscore:

Variant	Effect	Δscore
7:123949868:AAAG:A	acceptor_gain	1.0000
7:123949868:AAAGG:A	acceptor_gain	1.0000
7:123955082:GTATG:G	donor_gain	1.0000
7:123949867:CAAA:C	acceptor_loss	0.9900
7:123949869:A:G	acceptor_gain	0.9900
7:123949869:AAG:A	acceptor_gain	0.9900
7:123949870:A:AG	acceptor_gain	0.9900
7:123949870:AG:A	acceptor_gain	0.9900
7:123949871:G:A	acceptor_gain	0.9900
7:123949871:G:GA	acceptor_loss	0.9900
7:123949871:G:GG	acceptor_gain	0.9900
7:123949871:GGGAT:G	acceptor_gain	0.9900
7:123949984:G:GC	donor_loss	0.9900
7:123949985:T:G	donor_loss	0.9900
7:123954991:TTCCA:T	acceptor_loss	0.9900
7:123954992:TCCAG:T	acceptor_loss	0.9900
7:123954993:CCAG:C	acceptor_loss	0.9900
7:123954994:CAGGA:C	acceptor_loss	0.9900
7:123954995:A:AG	acceptor_gain	0.9900
7:123954995:A:C	acceptor_loss	0.9900
7:123954996:G:A	acceptor_loss	0.9900
7:123954996:G:GG	acceptor_gain	0.9900
7:123954996:GGAT:G	acceptor_gain	0.9900
7:123955083:TATGG:T	donor_loss	0.9900
7:123955086:GGTAA:G	donor_loss	0.9900
7:123955087:G:C	donor_loss	0.9900
7:123955088:T:TC	donor_loss	0.9900
7:123955089:A:AG	donor_loss	0.9900
7:123949868:A:AG	acceptor_gain	0.9800
7:123949869:AAGG:A	acceptor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001471 (7:123932894 A>G), RS1000002700 (7:123964453 A>G), RS1000060431 (7:123939217 C>T), RS1000175134 (7:123942520 G>C), RS1000200476 (7:123943944 T>C,G), RS1000306298 (7:123951291 T>C), RS1000441943 (7:123950885 G>A), RS1000450142 (7:123924538 A>G), RS1000504497 (7:123944417 A>G,T), RS1000513556 (7:123971061 C>T), RS1000562555 (7:123950042 A>G), RS1000667550 (7:123937571 A>G,T), RS1000737071 (7:123937290 A>G), RS1000792031 (7:123937464 G>A,T), RS1000845464 (7:123956401 T>C,G)

Disease associations

OMIM: gene MIM:600930 | 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
GCST008764_12	Perceived intensity of neohesperidin dihydrochalcone	3.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

3 total (human), top 3 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Tetrachlorodibenzodioxin	increases expression	1

Clinical trials (associated diseases)

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