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

2010-03-01   Asli Sade , Sreeparna Banerjee 

Department of Biology, Middle East Technical University, Ankara 06531, Turkey

Identity

HGNC
LOCATION
7q31.32
LOCUSID
ALIAS
HEL-S-96n,HYA1,HYAL1,HYAL3,HYAL5,PH-20,PH20,SPAG15

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.
Atlas Image
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.

Proteins

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 name
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 name
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 name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
92889011997In vitro mutagenesis of PH-20 hyaluronidase from human sperm.Arming S et al
119227352002Expression of PH-20 in normal and neoplastic breast tissue.Beech DJ et al
117312692001The dual functions of GPI-anchored PH-20: hyaluronidase and intracellular signaling.Cherr GN et al
167136802006Hyaluronidase and CD44 hyaluronan receptor expression in squamous cell laryngeal carcinoma.Christopoulos TA et al
117312672001The six hyaluronidase-like genes in the human and mouse genomes.Csoka AB et al
90604061997The 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 et al
158043582005Transcription of the human and rodent SPAM1 / PH-20 genes initiates within an ancient endogenous retrovirus.Dunn CA et al
129322972003SPAM1 (PH-20) protein and mRNA expression in the epididymides of humans and macaques: utilizing laser microdissection/RT-PCR.Evans EA et al
107220162000PH20: a novel tumor marker for laryngeal cancer.Godin DA et al
174467142007Expression 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 et al
85757801995Expression analysis, genomic structure, and mapping to 7q31 of the human sperm adhesion molecule gene SPAM1.Jones MH et al
87555621996Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.Liu D et al
99338251998Expression profile of hyaluronidase mRNA transcripts in the kidney and in renal cells.Sun L et al
117469652001Identification of a hyaluronic acid (HA) binding domain in the PH-20 protein that may function in cell signaling.Vines CA et al
126726662003Mouse Spam1 (PH-20) is a multifunctional protein: evidence for its expression in the female reproductive tract.Zhang H et al
118452842001Spam1 (PH-20) mutations and sperm dysfunction in mice with the Rb(6.16) or Rb(6.15) translocation.Zheng Y et al
104232921999Characterization of the genomic structure of the murine Spam1 gene and its promoter: evidence for transcriptional regulation by a cAMP-responsive element.Zheng Y et al

Other Information

Locus ID:

NCBI: 6677
MIM: 600930
HGNC: 11217
Ensembl: ENSG00000106304

Variants:

dbSNP: 6677
ClinVar: 6677
TCGA: ENSG00000106304
COSMIC: SPAM1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000106304ENST00000223028P38567
ENSG00000106304ENST00000223028Q5D1J4
ENSG00000106304ENST00000340011P38567
ENSG00000106304ENST00000402183P38567
ENSG00000106304ENST00000413927C9J2X5
ENSG00000106304ENST00000439500P38567
ENSG00000106304ENST00000439500Q5D1J4
ENSG00000106304ENST00000460182P38567
ENSG00000106304ENST00000460182Q5D1J4

Expression (GTEx)

0
5
10
15
20

Pathways

PathwaySourceExternal ID
Glycosaminoglycan degradationKEGGko00531
Glycosaminoglycan degradationKEGGhsa00531
Metabolic pathwaysKEGGhsa01100
Dermatan sulfate degradationKEGGhsa_M00076
Chondroitin sulfate degradationKEGGhsa_M00077
Dermatan sulfate degradationKEGGM00076
Chondroitin sulfate degradationKEGGM00077
ReproductionREACTOMER-HSA-1474165
FertilizationREACTOMER-HSA-1187000
Interaction With Cumulus CellsREACTOMER-HSA-2534343

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
234635252013Digestion products of the PH20 hyaluronidase inhibit remyelination.41
232098332012The molecular chaperone HSPA2 plays a key role in regulating the expression of sperm surface receptors that mediate sperm-egg recognition.24
206348912010Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia.18
247784422014Recombinant human hyaluronidase PH20 does not stimulate an acute inflammatory response and inhibits lipopolysaccharide-induced neutrophil recruitment in the air pouch model of inflammation.15
232478132013Investigation of the mechanisms by which the molecular chaperone HSPA2 regulates the expression of sperm surface receptors involved in human sperm-oocyte recognition.11
129322972003SPAM1 (PH-20) protein and mRNA expression in the epididymides of humans and macaques: utilizing laser microdissection/RT-PCR.6
252094252016Discovery of human posterior head 20 (hPH20) and homo sapiens sperm acrosome associated 1 (hSPACA1) immunocontraceptive epitopes and their effects on fertility in male and female mice.0

Citation

Asli Sade ; Sreeparna Banerjee

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

Atlas Genet Cytogenet Oncol Haematol. 2010-03-01

Online version: http://atlasgeneticsoncology.org/gene/42361/spam1