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SPAM1 (sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding))

Written2010-03Asli Sade, Sreeparna Banerjee
Department of Biology, Middle East Technical University, Ankara 06531, Turkey

(Note : for Links provided by Atlas : click)


Alias (NCBI)EC
HGNC Alias symbHYAL5
HGNC Alias namePH-20 hyaluronidase
HGNC Previous namesperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding)
LocusID (NCBI) 6677
Atlas_Id 42361
Location 7q31.32  [Link to chromosome band 7q31]
Location_base_pair Starts at 123925241 and ends at 123960046 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping SPAM1.png]
Local_order According to NCBI Map Viewer, genes flanking SPAM1 in centromere to telomere direction on 7q31.3 are:
- HYALP1 7q31.3 hyaluronoglucosaminidase pseudogene 1
- HYAL4 7q31.3 hyaluronoglucosaminidase 4
- SPAM1 7q31.3 sperm adhesion molecule 1
- TMEM229A 7q31.32 transmembrane protein 229A
- hCG_1651160 7q31.33 SSU72 RNA polymerase II CTD phosphatase homolog pseudogene
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note SPAM1 is a glycosyl-phosphatidyl inositol (GPI)-anchored enzyme found in all mammalian spermatozoa. The protein has a hyaluronidase activity that enables sperm to penetrate the cumulus, a role in zona pellucida binding and also participates in Ca2+ signaling associated acrosomal exocytosis.


Note The human genome contains six hyaluronidase like genes. Three of them (HYAL1, HYAL2 and HYAL3) are clustered on chromosome 3p21.3 and the other three (HYAL4, SPAM1 and HYALP1) are clustered on chromosome 7q31.3. Of the three genes on chromosome 7q31.3, HYALP1 is an expressed pseudogene. The extensive homology between the six hyaluronidase genes suggests an ancient gene duplication event before the emergence of modern mammals.
  The diagram of SPAM1 transcript variant 1. The red boxes represent the exons (in scale) and exon numbers are given below the boxes.
Description According to Entrez Gene, SPAM1 gene maps to locus NC_000007 and spans a region of 46136 bp. According to Spidey (mRNA to genomic sequence alignment tool), SPAM1 has 7 exons, the sizes being 78, 112, 1160, 90, 441, 99 and 404.
Transcription The SPAM1 mRNA has two isoforms; transcript variant 1 (NM_003117) a 2395 bp mRNA and transcript variant 2 (NM_153189) a 2009 bp mRNA. The variant 2 uses an alternate in-frame splice site in the 3' coding region, compared to variant 1, resulting in a shorter C-terminus.
The promoter region of SPAM1 has been shown to contain a CRE (cAMP-responsive element) sequence which is a binding site for CREM (cAMP-responsive element modulator) and thus Spam1 is under a cAMP-dependent transcriptional regulation. No TATA or CCAAT boxes were found in the promoter region of SPAM1. The testis-specific promoters of the human and mouse SPAM1 genes are derived from a sequence that was originally part of an ERV pol gene.
Pseudogene The human SPAM1 pseudogene HYALP1 is located on chromosome 7q31.3.


Note Two sperm adhesion isoforms exist; one is 511 aa long isoform 1 and the other 509 aa long isoform 2. When the two isoforms are aligned the sequences are 100% identical and no functional difference has been reported.
Description SPAM1 is a 68 kDa protein that belongs to glycosyl hydrolase 56 family. This family of enzymes has hyaluronidase activity which hydrolyses the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. Sperm hyaluronidase is active at neutral and acidic pHs which results from different active sites in the hyaluronidase domain at the N-terminus of the protein. The hyaluronidase domain also contains a hyaluronic acid (HA) binding site that plays a role in the signaling pathway leading to acrosomal exocytosis. The protein also contains a zona binding domain at the C-terminal end.
Expression According to GNF Expression Atlas 2 Data from U133A and GNF1H Chips, SPAM1 expression is widely limited to testis and epididymis but it was also found to be expressed in murine kidney and female reproductive tract. Both rare and abundant SPAM1 transcripts have been found in neoplastic breast tissue and in a number of other cancers including pharyngeal astatic melanomas and gliomas. In normal somatic cells rare transcripts have been found in breast tissue and in fetal, placental, and prostate cDNA libraries.
Localisation SPAM1 is located on the sperm surface and in the lysosome-derived acrosome, where it is bound to the inner acrosomal membrane. The acrosomal membrane SPAM1 differs biochemically from the one on the sperm surface.
Function SPAM1 is a multifunctional protein; a hyaluronidase that acts in penetrating the cumulus, a receptor for hyaluronic acid induced cell signaling which leads to acrosomal exocytosis and a receptor for the zona pellucida surrounding the oocyte. The zona pellucida recognition function is ascribed to the inner acrosomal membrane SPAM1. The neutral enzyme activity of plasma membrane SPAM1, which is GPI anchored, is responsible for local degradation of the cumulus ECM during sperm penetration. Plasma membrane SPAM1 mediates HA-induced sperm signaling via the HA binding domain. SPAM1 is also secreted by the epithelial cells of the epididymis and has a role in sperm maturation. In addition SPAM1 is implicated in fluid reabsorption and urine concentration in kidney.
Homology - Pan troglodytes sperm adhesion molecule 1 (SPAM1)
- Canis lupus familiaris sperm adhesion molecule 1 (SPAM1)
- Bos taurus sperm adhesion molecule 1 (SPAM1)
- Mus musculus hyaluronoglucosaminidase 5 (Hyal5)
- Mus musculus sperm adhesion molecule 1 (SPAM1)
- Rattus norvegicus sperm adhesion molecule 1 (HYALP_RAT)
- Gallus gallus sperm adhesion molecule 1 (SPAM1)
- Danio rerio sperm adhesion molecule 1 (Spam1)


Note According to dbSNP, one validated missense SNP for SPAM1 is found in the 47th aa position causing a V to A (rs34633019) substitution. Other SNPs causing synonymous changes are: rs34404662 A/G substitution at the 3rd amino acid residue (Val), rs2285996 A/G substitution at the 184th amino acid residue (Lys) and rs34978112 C/T substitution at the 330th amino acid residue (Ala). No clinical associations with these SNPs have been reported.
Germinal In mice bearing Robertsonian translocation Rb(6.15) and (6.16), reduced Spam1 hyaluronidase activity was found to cause sperm dysfunction. It was proposed that entrapment of spontaneous Spam1 mutations, owing to recombination suppression near the Rb junctions was the major effect.
According to in vitro mutagenesis experiments the following mutations were detected to have functional consequences:
- D146N: 80% loss of activity
- E148Q: loss of activity
- R211G: 90% loss of activity
- E284Q: loss of activity
- R287T: loss of activity

Implicated in

Entity Breast cancer
Oncogenesis Increased levels of SPAM1 are noted in invasive and metastatic breast cancer compared to ductal carcinoma in situ (DCIS). Tumors from African American women with invasive and metastatic breast cancer showed higher levels of SPAM1 than Caucasians. Varying levels of SPAM1 in mammary tissue may contribute to early invasion and metastasis of breast cancer.
Entity Laryngeal cancer
Oncogenesis SPAM1 expression was found to be significantly elevated in primary laryngeal cancer tissue and even higher in metastatic lesions compared with normal laryngeal tissue. SPAM1 may therefore be a useful tumor marker and prognostic tool for laryngeal cancer. In squamous cell laryngeal carcinoma aberrant expression of SPAM1 at late stages of cancer was detected.
Entity Colon Cancer
Oncogenesis SPAM1 mRNA was present in mRNA from four biopsies obtained from patients with colorectal cancers. Normal colonic mucosal tissues obtained from the same patients did not express SPAM1 mRNA. In metastatic colon carcinoma cell lines but not in non-metastatic cell lines, SPAM1 expression was detected. Strong angiogenesis developed in four of five animals injected with SPAM1+ colon carcinoma VAC05 cells. However, only one of five animals injected with SPAM1- VAC06 cells developed significant angiogenesis.
Entity Melanoma
Oncogenesis SPAM1 expression is seen in metastatic melanoma but not in non-metastatic melanoma cell lines (SMMU-2 and SMMU-1 respectively). SPAM1+ human melanoma cell line SMMU-2 but not SPAM1- SMMU-1 cells induced angiogenesis in mice cornea although the exact mechanisms of how SPAM1 induces angiogenesis is not known.


In vitro mutagenesis of PH-20 hyaluronidase from human sperm.
Arming S, Strobl B, Wechselberger C, Kreil G.
Eur J Biochem. 1997 Aug 1;247(3):810-4.
PMID 9288901
Expression of PH-20 in normal and neoplastic breast tissue.
Beech DJ, Madan AK, Deng N.
J Surg Res. 2002 Apr;103(2):203-7.
PMID 11922735
The dual functions of GPI-anchored PH-20: hyaluronidase and intracellular signaling.
Cherr GN, Yudin AI, Overstreet JW.
Matrix Biol. 2001 Dec;20(8):515-25. (REVIEW)
PMID 11731269
Hyaluronidase and CD44 hyaluronan receptor expression in squamous cell laryngeal carcinoma.
Christopoulos TA, Papageorgakopoulou N, Theocharis DA, Mastronikolis NS, Papadas TA, Vynios DH.
Biochim Biophys Acta. 2006 Jul;1760(7):1039-45. Epub 2006 Apr 4.
PMID 16713680
The six hyaluronidase-like genes in the human and mouse genomes.
Csoka AB, Frost GI, Stern R.
Matrix Biol. 2001 Dec;20(8):499-508. (REVIEW)
PMID 11731267
The mouse Spam1 maps to proximal chromosome 6 and is a candidate for the sperm dysfunction in Rb(6.16)24Lub and Rb(6.15)1Ald heterozygotes.
Deng X, Moran J, Copeland NG, Gilbert DJ, Jenkins NA, Primakoff P, Martin-DeLeon PA.
Mamm Genome. 1997 Feb;8(2):94-7.
PMID 9060406
Transcription of the human and rodent SPAM1 / PH-20 genes initiates within an ancient endogenous retrovirus.
Dunn CA, Mager DL.
BMC Genomics. 2005 Apr 1;6(1):47.
PMID 15804358
SPAM1 (PH-20) protein and mRNA expression in the epididymides of humans and macaques: utilizing laser microdissection/RT-PCR.
Evans EA, Zhang H, Martin-DeLeon PA.
Reprod Biol Endocrinol. 2003 Aug 6;1:54.
PMID 12932297
PH20: a novel tumor marker for laryngeal cancer.
Godin DA, Fitzpatrick PC, Scandurro AB, Belafsky PC, Woodworth BA, Amedee RG, Beech DJ, Beckman BS.
Arch Otolaryngol Head Neck Surg. 2000 Mar;126(3):402-4.
PMID 10722016
Expression of SPAM1 (PH-20) in the murine kidney is not accompanied by hyaluronidase activity: evidence for potential roles in fluid and water reabsorption.
Grigorieva A, Griffiths GS, Zhang H, Laverty G, Shao M, Taylor L, Martin-DeLeon PA.
Kidney Blood Press Res. 2007;30(3):145-55. Epub 2007 Apr 19.
PMID 17446714
Expression analysis, genomic structure, and mapping to 7q31 of the human sperm adhesion molecule gene SPAM1.
Jones MH, Davey PM, Aplin H, Affara NA.
Genomics. 1995 Oct 10;29(3):796-800.
PMID 8575780
Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.
Liu D, Pearlman E, Diaconu E, Guo K, Mori H, Haqqi T, Markowitz S, Willson J, Sy MS.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7832-7.
PMID 8755562
Expression profile of hyaluronidase mRNA transcripts in the kidney and in renal cells.
Sun L, Feusi E, Sibalic A, Beck-Schimmer B, Wuthrich RP.
Kidney Blood Press Res. 1998;21(6):413-8.
PMID 9933825
Identification of a hyaluronic acid (HA) binding domain in the PH-20 protein that may function in cell signaling.
Vines CA, Li MW, Deng X, Yudin AI, Cherr GN, Overstreet JW.
Mol Reprod Dev. 2001 Dec;60(4):542-52.
PMID 11746965
Mouse Spam1 (PH-20) is a multifunctional protein: evidence for its expression in the female reproductive tract.
Zhang H, Martin-DeLeon PA.
Biol Reprod. 2003 Aug;69(2):446-54. Epub 2003 Apr 2.
PMID 12672666
Spam1 (PH-20) mutations and sperm dysfunction in mice with the Rb(6.16) or Rb(6.15) translocation.
Zheng Y, Deng X, Zhao Y, Zhang H, Martin-DeLeon PA.
Mamm Genome. 2001 Nov;12(11):822-9.
PMID 11845284
Characterization of the genomic structure of the murine Spam1 gene and its promoter: evidence for transcriptional regulation by a cAMP-responsive element.
Zheng Y, Martin-Deleon PA.
Mol Reprod Dev. 1999 Sep;54(1):8-16.
PMID 10423292


This paper should be referenced as such :
Sade, A ; Banerjee, S
SPAM1 (sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding))
Atlas Genet Cytogenet Oncol Haematol. 2010;14(12):1160-1162.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)SPAM1   11217
Entrez_Gene (NCBI)SPAM1    sperm adhesion molecule 1
AliasesHEL-S-96n; HYA1; HYAL1; HYAL3; 
HYAL5; PH-20; PH20; SPAG15
GeneCards (Weizmann)SPAM1
Ensembl hg19 (Hinxton)ENSG00000106304 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000106304 [Gene_View]  ENSG00000106304 [Sequence]  chr7:123925241-123960046 [Contig_View]  SPAM1 [Vega]
ICGC DataPortalENSG00000106304
TCGA cBioPortalSPAM1
Genatlas (Paris)SPAM1
SOURCE (Princeton)SPAM1
Genetics Home Reference (NIH)SPAM1
Genomic and cartography
GoldenPath hg38 (UCSC)SPAM1  -     chr7:123925241-123960046 +  7q31.32   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SPAM1  -     7q31.32   [Description]    (hg19-Feb_2009)
GoldenPathSPAM1 - 7q31.32 [CytoView hg19]  SPAM1 - 7q31.32 [CytoView hg38]
Genome Data Viewer NCBISPAM1 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AK292229 AY920278 AY920279 AY920280 AY920281
RefSeq transcript (Entrez)NM_001174044 NM_001174045 NM_001174046 NM_003117 NM_153189
Consensus coding sequences : CCDS (NCBI)SPAM1
Gene ExpressionSPAM1 [ NCBI-GEO ]   SPAM1 [ EBI - ARRAY_EXPRESS ]   SPAM1 [ SEEK ]   SPAM1 [ MEM ]
Gene Expression Viewer (FireBrowse)SPAM1 [ Firebrowse - Broad ]
GenevisibleExpression of SPAM1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6677
GTEX Portal (Tissue expression)SPAM1
Human Protein AtlasENSG00000106304-SPAM1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP38567   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP38567  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP38567
Catalytic activity : Enzyme3.2.1.35 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
Domains : Interpro (EBI)Aldolase_TIM    Glycoside_hydrolase_SF    Hyaluronidase    Hyaluronidase_PH20/Hyal5   
Domain families : Pfam (Sanger)Glyco_hydro_56 (PF01630)   
Domain families : Pfam (NCBI)pfam01630   
Conserved Domain (NCBI)SPAM1
AlphaFold pdb e-kbP38567   
Human Protein Atlas [tissue]ENSG00000106304-SPAM1 [tissue]
Protein Interaction databases
IntAct (EBI)P38567
Ontologies - Pathways
Ontology : AmiGOacrosomal vesicle  hyalurononglucosaminidase activity  plasma membrane  carbohydrate metabolic process  cell adhesion  binding of sperm to zona pellucida  fusion of sperm to egg plasma membrane involved in single fertilization  hyaluronan catabolic process  anchored component of membrane  cytoplasmic vesicle  sperm-egg recognition  
Ontology : EGO-EBIacrosomal vesicle  hyalurononglucosaminidase activity  plasma membrane  carbohydrate metabolic process  cell adhesion  binding of sperm to zona pellucida  fusion of sperm to egg plasma membrane involved in single fertilization  hyaluronan catabolic process  anchored component of membrane  cytoplasmic vesicle  sperm-egg recognition  
Pathways : KEGGGlycosaminoglycan degradation   
REACTOMEP38567 [protein]
REACTOME PathwaysR-HSA-2534343 [pathway]   
NDEx NetworkSPAM1
Atlas of Cancer Signalling NetworkSPAM1
Wikipedia pathwaysSPAM1
Orthology - Evolution
GeneTree (enSembl)ENSG00000106304
Phylogenetic Trees/Animal Genes : TreeFamSPAM1
Homologs : HomoloGeneSPAM1
Homology/Alignments : Family Browser (UCSC)SPAM1
Gene fusions - Rearrangements
Fusion : QuiverSPAM1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSPAM1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SPAM1
Exome Variant ServerSPAM1
GNOMAD BrowserENSG00000106304
Varsome BrowserSPAM1
ACMGSPAM1 variants
Genomic Variants (DGV)SPAM1 [DGVbeta]
DECIPHERSPAM1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSPAM1 
ICGC Data PortalSPAM1 
TCGA Data PortalSPAM1 
Broad Tumor PortalSPAM1
OASIS PortalSPAM1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSPAM1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DSPAM1
Mutations and Diseases : HGMDSPAM1
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)SPAM1
DoCM (Curated mutations)SPAM1
CIViC (Clinical Interpretations of Variants in Cancer)SPAM1
NCG (London)SPAM1
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry SPAM1
NextProtP38567 [Medical]
Target ValidationSPAM1
Huge Navigator SPAM1 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDSPAM1
Pharm GKB GenePA36053
Clinical trialSPAM1
DataMed IndexSPAM1
PubMed23 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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