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

Identity

Other namesEC 3.2.1.35
HYA1
HYAL1
HYAL3
HYAL5
Hyal-PH20
MGC26532
PH-20
PH20
SPAG15
HGNC (Hugo) SPAM1
LocusID (NCBI) 6677
Location 7q31.32
Location_base_pair Starts at 123565286 and ends at 123600100 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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
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.

DNA/RNA

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.

Protein

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)

Mutations

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.
  

External links

Nomenclature
HGNC (Hugo)SPAM1   11217
Cards
AtlasSPAM1ID42361ch7q31
Entrez_Gene (NCBI)SPAM1  6677  sperm adhesion molecule 1 (PH-20 hyaluronidase, zona pellucida binding)
GeneCards (Weizmann)SPAM1
Ensembl (Hinxton)ENSG00000106304 [Gene_View]  chr7:123565286-123600100 [Contig_View]  SPAM1 [Vega]
AceView (NCBI)SPAM1
Genatlas (Paris)SPAM1
WikiGenes6677
SOURCE (Princeton)NM_001174044 NM_001174045 NM_001174046 NM_003117 NM_153189
Genomic and cartography
GoldenPath (UCSC)SPAM1  -  7q31.32   chr7:123565286-123600100 +  7q31.3   [Description]    (hg19-Feb_2009)
EnsemblSPAM1 - 7q31.3 [CytoView]
Mapping of homologs : NCBISPAM1 [Mapview]
OMIM600930   
Gene and transcription
Genbank (Entrez)AK292229 AY920278 AY920279 AY920280 AY920281
RefSeq transcript (Entrez)NM_001174044 NM_001174045 NM_001174046 NM_003117 NM_153189
RefSeq genomic (Entrez)AC_000068 AC_000139 NC_000007 NC_018918 NT_007933 NT_079596 NW_001839071 NW_004929332
Consensus coding sequences : CCDS (NCBI)SPAM1
Cluster EST : UnigeneHs.121494 [ NCBI ]
CGAP (NCI)Hs.121494
Alternative Splicing : Fast-db (Paris)GSHG0027684
Alternative Splicing GalleryENSG00000106304
Gene ExpressionSPAM1 [ NCBI-GEO ]     SPAM1 [ SEEK ]   SPAM1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP38567 (Uniprot)
NextProtP38567  [Medical]
With graphics : InterProP38567
Splice isoforms : SwissVarP38567 (Swissvar)
Catalytic activity : Enzyme3.2.1.35 [ Enzyme-Expasy ]   3.2.1.353.2.1.35 [ IntEnz-EBI ]   3.2.1.35 [ BRENDA ]   3.2.1.35 [ KEGG ]   
Domains : Interpro (EBI)Aldolase_TIM    Glycoside_hydrolase_SF    Hyaluronidase    Hyaluronidase_PH20   
Related proteins : CluSTrP38567
Domain families : Pfam (Sanger)Glyco_hydro_56 (PF01630)   
Domain families : Pfam (NCBI)pfam01630   
DMDM Disease mutations6677
Blocks (Seattle)P38567
Human Protein AtlasENSG00000106304
Peptide AtlasP38567
HPRD02958
IPIIPI00219717   IPI00170588   IPI00926802   
Protein Interaction databases
DIP (DOE-UCLA)P38567
IntAct (EBI)P38567
FunCoupENSG00000106304
BioGRIDSPAM1
InParanoidP38567
Interologous Interaction database P38567
IntegromeDBSPAM1
STRING (EMBL)SPAM1
Ontologies - Pathways
Ontology : AmiGOhyalurononglucosaminidase activity  plasma membrane  carbohydrate metabolic process  cell adhesion  single fertilization  binding of sperm to zona pellucida  fusion of sperm to egg plasma membrane  anchored to membrane  multicellular organism reproduction  sperm-egg recognition  
Ontology : EGO-EBIhyalurononglucosaminidase activity  plasma membrane  carbohydrate metabolic process  cell adhesion  single fertilization  binding of sperm to zona pellucida  fusion of sperm to egg plasma membrane  anchored to membrane  multicellular organism reproduction  sperm-egg recognition  
Pathways : KEGGGlycosaminoglycan degradation   
REACTOMESPAM1
Protein Interaction DatabaseSPAM1
Wikipedia pathwaysSPAM1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)SPAM1
SNP (GeneSNP Utah)SPAM1
SNP : HGBaseSPAM1
Genetic variants : HAPMAPSPAM1
1000_GenomesSPAM1 
ICGC programENSG00000106304 
Somatic Mutations in Cancer : COSMICSPAM1 
CONAN: Copy Number AnalysisSPAM1 
Mutations and Diseases : HGMDSPAM1
OMIM600930   
GENETestsSPAM1
Disease Genetic AssociationSPAM1
Huge Navigator SPAM1 [HugePedia]  SPAM1 [HugeCancerGEM]
Genomic VariantsSPAM1  SPAM1 [DGVbeta]
Exome VariantSPAM1
dbVarSPAM1
ClinVarSPAM1
snp3D : Map Gene to Disease6677
General knowledge
Homologs : HomoloGeneSPAM1
Homology/Alignments : Family Browser (UCSC)SPAM1
Phylogenetic Trees/Animal Genes : TreeFamSPAM1
Chemical/Protein Interactions : CTD6677
Chemical/Pharm GKB GenePA36053
Clinical trialSPAM1
Cancer Resource (Charite)ENSG00000106304
Other databases
Probes
Litterature
PubMed19 Pubmed reference(s) in Entrez
CoreMineSPAM1
iHOPSPAM1

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written03-2010Asli Sade, Sreeparna Banerjee
Department of Biology, Middle East Technical University, Ankara 06531, Turkey

Citation

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. March 2010 .
URL : http://AtlasGeneticsOncology.org/Genes/SPAM1ID42361ch7q31.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44921/1/03-2010-SPAM1ID42361ch7q31.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:24:41 CEST 2014

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