Written | 2007-09 | Juliette Gimenez, François Mallet |
UMR 2714 CNRS-bioMörieux, IFR128 BioSciences Lyon-Gerland, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France |
Identity |
Alias_names | ERVWE1 |
endogenous retroviral family W, env(C7), member 1 | |
endogenous retrovirus group W, member 1 | |
endogenous retrovirus group W member 1 | |
Alias_symbol (synonym) | HERV-W |
HERV-W-ENV | |
HERVW | |
HERV-7q | |
envW | |
Other alias | env |
enverin | |
Env-W | |
HERV-W_7q21.2 provirus ancestral Env polyprotein precursor | |
Syncytin | |
Syncytin-1 | |
HGNC (Hugo) | ERVW-1 |
LocusID (NCBI) | 30816 |
Atlas_Id | 40497 |
Location | - [Link to chromosome band ] |
Location_base_pair | Starts at 92468381 and ends at 92471424 bp from pter ( according to hg19-Feb_2009) [Mapping ERVW-1.png] |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
ERVW-1 (FGFR1) / ERO1A (14q22.1) | STPG1 (1p36.11) / ERVW-1 () | STPG1 (1p36.11) / ERVW-1 (7q21.2) | |
Note | Sequences of retroviral origin represent about 8% of the human genome. There are at least 31 families of human endogenous retroviruses (HERVs). Each family derived from an independent infection of the germ line by an exogenous virus during the evolution of the human lineage. The infectious retrovirus founding the contemporary HERV-W family entered the human ancestor genome after the divergence between Catarrhini and Platyrrhini, i.e., less than 40 million years ago. The spread of the HERV-W family into the genome essentially results from events of intracellular retrotransposition of transcriptionally active copies, a phenomenon mediated either by their own reverse transcriptase (RT) machinery or by RT from LINE elements. Generally, due to the absence of a selective pressure, HERV-W elements have accumulated inactivating substitutions (frame-shifts, nonsense mutations), leading to complex multicopy families whose transmission is exclusively Mendelian. Thus, the contemporary HERV-W family consists of collections of heterogeneous elements, ranging from full-length defective proviruses (gag, pol, and env genes flanked at both extremities by two long terminal repeats (LTRs)) to isolated LTRs derived from recombination events. The human endogenous retrovirus HERV-W multicopy family includes a unique proviral locus, termed ERVWE1, which contains gag and pol pseudogenes and has retained a full-length envelope open reading frame (ORF) also named Syncytin or Syncytin-1. ERVWE1 is a bona fide gene involved in hominoid placental physiology. |
DNA/RNA |
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Figure 1: ERVWE1 provirus genomic structure and 7q21.2 chromosomal environment: Flanking black boxes correspond to the 24th exon and the 5th exon of the PEX1 and ODAG genes, respectively, defining a LTR element-rich region of 30 kb in human 7q21.2. Isolated LTR elements are depicted as red boxes (MaLR LTR) and green boxes (HERV-P LTR). U3 (white) , R (hatched) and U5 (dark grey) regions of 5' and 3' LTRs of ERVWE1 provirus are indicated. U3, R and U5 regions of 5' and 3' LTRs of HERV-H provirus LTRs are labelled in purple. Short direct repeats (light grey and dark grey arrows) located at each boundary of ERVWE1 and HERV-H proviruses indicates that integration of each element was mediated by an HERV-family specific reverse transcriptase. Pseudogenes (labelled Δ) are shown as boxes. The Syncytin-1 open reading frame is depicted by a large orange arrow. A 2-kb intron (black line) is located just downstream of the 5' ERVWE1 LTR. A double arrow indicates the ERVWE1 transcriptional regulatory region (see figure 3). Figure 2: ERVWE1 evolution and selection in primates. Figure 3: ERVWE1/Syncytin-1 transcriptional regulatory element: ERVWE1/Syncytin-1 expression is regulated by a bipartite element consisting of a cyclic AMP-inducible LTR retroviral promoter (ERVWE1 5'LTR U3 region) adjacent to an upstream regulatory element (URE) of composite origin. This URE consists of a 208 bp non-retroviral, non-repeated/transposable cellular sequence (non-TE region) and a 228pb MaLR LTR containing a trophoblast specific enhancer (TSE) which confers a high level of expression and placental tropism. True (top black boxes) and putative (bottom grey boxes) transcription factor binding sites along ERVWE1 5'LTR and URE are indicated. The positive (+) or negative (+) involvement of regulatory domains in placental tissue is annotated below the schematic representation. The CAP transcription initiation site (arrow) is located at the 5' end of the R region. Figure 4: ERVWE1 splicing strategy in placenta: The CAP transcription initiation site (right arrow) is located at the 5' end of the R region of the 5'LTR. The polyadenylation signal (left arrow) is located toward the 3' end of the R region belonging to the 3'LTR. ERVWE1 produces three major single-spliced transcripts in placental tissue, the subgenomic 7.4-kb and 3.1-kb mRNAs and the fully-spliced 1.3-kb mRNA. Only the 3.1-kb variant is responsible for Syncytin-1 translation. Splice donor (SD) and acceptor (SA) sites are indicated by right and left arrows, respectively. SD and SA were identified by screening a placental cDNA library. SD2 site was identified in a single clone. | |
Description | DNA STRUCTURE ERVWE1 is a 10.2-kb long full-length provirus integrated on chromosome 7q21.2. Like the proviral form of simple exogenous retroviruses, ERVWE1 is structurally composed of two long terminal repeats (LTRs), flanking the internal sequence containing gag, pol and env genes. Each LTR is composed of three regions, i.e. from 5' to 3'U3, R and U5. As in other proviruses, the U3 region of ERVWE1 5'LTR serves as proviral promoter and the R region of the 3'LTR acts as a polyadenylation signal. Both gag and pol genes, normally coding respectively for the matrix, capsid and nucleocapsid proteins, and for the viral enzymatic machinery, are disrupted by stop codons. Only the full-length env gene that codes for the envelope glycoprotein, Syncytin-1, is functionally preserved. In addition ERVWE1 contains a 2-kb intron, at the 5'LTR/gag junction, with no trivial homology or known function. CLASSIFICATION The current classification and nomenclature of ERVs is complex and varies between and within species. Retroviral classification is initially based on virion morphology during maturation and assembly of particles at the cell membrane. Accordingly, retroviruses are designated A-, B-, C- and D-type. ERVs are also classified on the basis of the similarity of their pol region to those of exogenous retroviruses. This point is illustrated in class I and II which group the pol MuLV-like (Murine Leukemia Virus) and the pol MMTV-like (Mouse Mammary Tumor Virus) ERVs, respectively. The International Committee on Taxonomy of Viruses (I.C.T.V., http://www.ncbi.nlm.nih.gov/ICTVdb/index.htm) has established seven genera of Retroviridae, Alpha-, Beta-, Gamma-, Delta-, Epsilon-retrovirus, Lentivirus and Spumavirus. The ERV nomenclature is heterogeneous and complex due to the difficulty to associate HERVs with physiopathological functions. It is mainly based on the Primer Binding Site (PBS) sequence, which is recognized by a specific tRNA whose one letter code then becomes the ERV suffix. As the PBS located 4 bp downstream from the U5 subdomain of the 5' ERVWE1 LTR showed extensive homology with the avian retroviruses PBS used by tRNATrp (single letter code: W) for minus-strand DNA synthesis, this family was tentatively named HERV-W. Phylogenetic trees within the pol region showed that the HERV-W family is related to ERV-9 and RTVL-H families and thus belongs to the class I endogenous retroviruses. The homologies within the pol and env genes with the murine type C and simian type D retroviruses, respectively, suggest a chimeric genome structure as described for baboon endogenous virus. Based on the size criteria, such a chimerism seemed to exist within the LTR: the 247-nt U3 and the 79- to 81-nt R elements were comparable to avian or type D retrovirus U3 and mammalian type C R elements, respectively, although the 410- to 455-nt U5 element remained unclassified as unusually long. According to the new classification, HERV-W elements belong to the genus of gammaretroviruses. No replication-competent elements could be found within the HERV-W family and no corresponding exogenous retrovirus have been characterized. EVOLUTION The MALR-e1 LTR portion located upstream of the ERVWE1 provirus has been shown to act as a trophoblast specific enhancer (TSE) that co-opted with the ERVWE1 5'LTR promoter, conferring on Syncytin-1 a specific and high activity in the placenta. This sequence is particularly conserved in humans as no polymorphism was observed in 48 sequences analyzed and is also strictly identical in all Hominidae sp. analyzed. In contrast, the portion located downstream of the provirus is different for each Hominidae species. The MaLR co-optation however seems to be Hominidae-specific, as in the gibbon (Hylobatidae), the MaLR is deficient in enhancer activity. In contrast the gibbon 5'LTR presents higher promoter activity. The 5'LTR exhibits an unusually low polymorphism (one variable site in 18.0 kb) as compared to the variability described for noncoding sequences (one every 0.47 kb) and repeated sequences (one every 0.31 kb), suggesting that there has been a selective sweep of this region. Conversely, the variability of the 3'LTR (one in 0.5 kb) is typical of repeated sequences. On line with this, the functional analysis of all U3 elements revealed that the human and other apes ERVWE1 5' LTRs were always more active in BeWo cells than the ERVWE1 3' LTRs. In all Hominoidae including the gibbon, the poly-A signal within the 3'LTR and the post-transcriptional regulation elements (env ATG context, 5' and 3' UTRs and splice sites including those for the env mRNA processing) are strictly identical. ERVWE1 env, Syncytin-1, was shown to be the most conserved env ORF of the 16 human proviruses (from 9 HERV families) still containing a env gene, even though it is the fourth oldest. The observed variability of the env ORF (one variable site every 2.2 kb) fell within the same range as the variability described for human coding sequences (one every 1.08-2.00 kb), highlighting that the behavior of this gene of retroviral origin is similar to any essential cellular gene, as opposed to infectious retroviruses or more generally RNA-based organism. The critical domains essential for classical retroviral envelope expression and function are highly conserved and clearly under functional constraint in the entire Hominoidae lineage. Most of the amino-acid changes in Syncytin-1 evolution are located in positions that are variable across env proteins (surface domain involved in receptor recognition and binding, intracytoplasmic tail involved in fusogenic activity regulation), which could represent gradual adjustment to its cellular function. Interestingly, based on sequences comparison and according to the most parsimonious scenario, one of the nonsense mutations found in Cercopithecus lineage, which eliminates the last 30 amino-acids of the env protein, occured in the Catarrhini ancestor but reverted in Hominoidae re-establishing the full-length env ORF. Furthermore, the ERVWE1 signature, which consists of four amino-acid (12-bp) deletions in the intracytoplasmic tail of the glycoprotein, were shown to be crucial for the envelope fusogenicity and all tested Hominoidae Syncytin-1 proteins present similar fusogenic activity in heterologous cell fusion assays. |
Transcription | RNA: SPLICING STRATEGY ERVWE1 full-length transcript, which would include the 2-kb intron, has never been detected. Though, ERVWE1 provirus produces 3 major monospliced transcripts. The first one is 7.4kb long. It corresponds to a splice of the 2kb intronic sequence (SD1/SA1), and thus contains the gag, pro/pol and env frames. The second one is 3.1kb long and results from the splice of the 2-kb intron, gag and pro/pol sequence (SD1/SA2). It thus contains only the env gene and is responsible for Syncytin-1 translation. The third produced transcript is a 1.3kb long fully spliced transcript (SD1/SA3). Other splice variants may theoretically exist, as at least another splice donor located at the env 5'UTR/ORF junction (SD2) was found to be used in association with the SA3 splice acceptor near the end of the ORF, eliminating the full env region in one placenta cDNA. Physiological transcription of the ERVWE1 locus has been detected in several tissues. Transcription levels however are mainly low as demonstrated by the need for sensitive detection techniques such as RT-PCR or EST analyses. Besides, placental and, to a lesser extent, testicular tissues have high ERVWE1 transcriptional activity as indicated by Northern blotting detection. In addition, ERVWE1/Syncytin-1 mRNAs have been detected in multiple sclerosis and tumoral tissues as well as cancerous cell lines. Table 1 shows all tissues where ERVWE1 and/or HERV-W env type transcripts have been reported. The finding of ERVWE1-specific transcripts are indicated, however the list may be not exhaustive. Moreover, these results must be treated with caution as (i) the biological significance of low expression levels could be questioned, and (ii) the Syncytin-1 sequence is present within both the 7.4 kb transcript (e.g. in the testis and placenta), and the Syncytin-1 producing 3.1 kb mRNA (to date observed exclusively in the placenta). TRANSCRIPTION Placental Syncytin-1 3.1kb mRNA expression occurs specifically in trophoblast cells (extravillous cytotrophoblasts, villous cytotrophoblasts, and the syncytiotrophoblast layer), but not in placenta parenchymal cells such as fibroblasts. The variation in Syncytin-1 mRNA levels during pregnancy has been the focus of several studies but results are to some extent controversial. Thus during the first trimester ERVWE1/Syncytin-1 expression is relatively high but stable. Conflicting results were obtained concerning the latter trimesters: (i) the level of expression is reduced during the second trimester and increases again in the third trimester to reach its highest level; (ii) this level increases progressively from the second to the third trimester and falls suddenly at term, (iii) at term, the expression level remains higher than in the first trimester or becomes lower. These discrepancies may be due to the amplification method (region amplified gag-pol versus env, ERVWE1 specificity, mRNA species specificity i.e. 7.4-, 3- kb or both) or the physiological sample. Indeed the observed loss of transcription during the second trimester is considered by the authors to be potentially an artefact linked to the medical -unknown- reason that lead to interruption of pregnancy in the second trimester. |
Protein |
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Figure 5: Organization of Syncytin-1 envelope glycoprotein: The surface (SU gp50, 22-317) and transmembrane (TM gp24, 318-538) domains are indicated in blue and yellow, respectively. They derive from the proteolytic cleavage of the gPr73 envelope precursor on the consensus furin cleavage site RNKR. The black dots indicate N-glycosylation sites (positions 169, 208, 214, 234, 242, 281, and 409). Gray boxes indicate the following conserved motifs: L, leader peptide (1-21); FP, fusion peptide (318-340); IM, putative immunosuppressive domain (377-396); TM (hatched), membrane anchorage domain (444-470). CYT, intracytoplasmic tail (471-538). The 124 N-terminal amino-acids of the HERV-W mature SU protein are sufficient to interact with the hASCT2 and hASCT1 amino-acid transporters and thus represent the receptor binding domain (RBD, medium blue). The 18AA-long SDGGGX2DX2R motif conserved among retroviruses of the same interference group (recognizing the same receptors) is indicated. Amine- and carboxy- heptad repeats (NHR 352-392, CHR 407-440) within the TM domain are indicated. They constitute the homotrimeric fusion active core structure which brings the phospholipid bilayers in two cells into close proximity, resulting in membrane fusion. The ERVWE1-specific LQMV deletion (del LQMV), absent from paralogous HERV-W copies, is indicated. This deletion within the CYT region is crucial for the Syncytin-1 constitutive fusogenic activity. CWIC and CX6CC motifs involved in disulfide bonding of SU and TM domains are indicated. | |
Description | ERVWE1 encodes a 538 amino-acid, 73-kDa glycosylated (53 kDa unglycosylated) envelope protein, Syncytin-1. Structurally, Syncytin-1 protein consists of a 20AA leader peptide at the amino end, a surface subunit (SU) (AA21-317) and a transmembrane subunit (TM) (AA318-538) at the carboxy end. Syncytin-1 is synthesized as a glycosylated gPr73 precursor that associates as a homotrimeric structure. Each precursor undergoes cleavage into two mature proteins: a gp50 surface unit (SU), and a gp24 transmembrane unit (TM). The cleavage occurs at a furin cleavage site (RNKR) located at the SU/TM junction. SU and TM are further covalently linked through a disulphid bond between CWIC and CX6CC motifs of the SU and TM respectively and reach the cellular membrane. SU is responsible for recognizing and binding to specific receptors on the host cell. TM presents a hydrophobic fusion peptide (AA320-340), and a fusion core made of N- and C-terminal heptad repeats (AA352-392 and AA407-440 respectively). Heptad repeats are also involved in the homotrimerization of the above-mentioned precursors. In addition TM contains an immunosuppressive region inside the C-terminal heptad repeat (AA377-396), a carboxy-transmembrane domain (AA444-469) for protein anchoring in the membrane and ends in a cytoplasmic tail. |
Function | - Protection against retroviral infection Syncytin-1 confers host cell resistance to infection by the spleen necrosis virus, an exogenous retrovirus whose envelope protein also uses RDR to enter cells. This phenomenon is due to a competitive binding mechanism to receptor sites called "receptor interference" and Syncytin-1 may confer host protection against infection by other exogenous retroviruses of the same interference group. - Ectopic retroviral infection Syncytin-1 can also pseudotype HIV-1 virions and confers on them a tropism for CD4 negative cells through interaction with the RDR receptors hASCT1 and hASCT2, that are widely expressed in diverse human cell types. However, the unusually long intracytoplasmic tail of Syncytin-1 as compared with other type D or C retroviruses makes it suboptimal for formation of infectious viral pseudotypes. Indeed it might interfere with efficient processing of the precursor and/or incorporation of the processed env glycoprotein into virions. |
Mutations |
Note | The conservation of ERVWE1 provirus genomic localisation and envelope open reading frame have been screened in 155 individuals. They are conserved in all individuals tested so far. Moreover, sequencing of critical elements of ERVWE1, including the env ORF but also LTR elements involved in transcriptional regulation and the splice sites necessary to generate subgenomic env mRNA, showed striking conservation among the 24 individuals (48 alleles) analysed. All the polymorphic variants of Syncytin-1 are fusogenic. Envelope allelic variants: Five mutations have been found within Syncytin-1 ORF. One is a synonymous mutation, while the four others are non-synonymous. These non-synonymous mutations are dispersed among five Syncytin-1 protein variants: V129-R138-S307-S477 (67% of the sequenced population), VRnS (25%), VqnS (4%), aRSS (2%), VqSf (2%). Each of the 24 analyzed individuals had at least one of the two major genotypes, i.e. VRSS and VRnS. Altogether, amino-acid variants (frequencies) are: AA129 V(0.979), a(0.021); AA138 R(0.9375), q(0.0625); AA307 S(0.7083), n(0.2917). All variants are functional and display the same fusogenicity. |
Germinal | None yet described |
Somatic | None yet described |
Implicated in |
Note | |
Entity | Placental diseases |
Note | Placental Morphogenesis: In physiological conditions, Syncytin-1 is exclusively expressed in placenta cells, i.e. in cytotrophoblasts and more markedly in the syncytiotrophoblast layer, but not in placenta mesenchyme. Syncytin-1 is directly involved in the fusion of placenta villous cytotrophoblasts into the syncytiotrophoblast, which constitutes the interface layer between the mother and the developing foetus. Fusion occurs following Syncytin-1 interaction with hASCT2/hATB/SCL1A5 receptors, whose expression is restricted to cytotrophoblast cells. Neither local nor temporal variations of RDR/ASCT2 expression in villous cytotrophoblast cells seems to regulate the fusion of placental trophoblast cells. Note that a modulation of cell surface expression of hASCT2 appears associated with syncytialization of BeWo cells. The level of Syncytin-1 protein in villous trophoblasts increases during early pregnancy (at least from the 6th to the 12th week of gestation) but is markedly reduced in late pregnancy. The syncytiotrophoblast is a polarized multinucleated layer, with its apical membrane facing the maternal blood circulation and the basal membrane facing the underlying cytotrophoblasts. Subcellular localization of synyctin-1 within the syncytiotrophoblast has been investigated but observations are controversial. Thus Syncytin-1 distribution has been described as diffuse within the syncytial layer with enhancement at the apical membrane during all trimesters of pregnancy, while another analysis reports basal membrane localisation. In the latter report, the apical localisation occurred only in syncytiotrophoblasts from women with pre-eclampsia (9 samples), and among them both basal and apical staining appeared once. Blocking Syncytin-1 proteins (at the translational or post-translational level) greatly reduced the fusion of cytotrophoblasts and syncytiotrophoblast formation but did not completely inhibit it indicating that there must be other proteins able to partially rescue the fusion of trophoblasts in the absence of Syncytin-1. One candidate is Syncytin-2, the envelope gene of an endogenous proviral copy from the HERV-FRD family. Indeed, even if this provirus is older than ERVWE1, the fusogenic property of Syncytin-2 has been also preserved and its expression is also high in the placenta. Syncytin-1 is also expressed, but at a much lower level, in all extravillous trophoblast types, at least in first trimester placentae. These cell types are CT cells of the implanting column, invading interstitial extravillous trophoblastic cells, multinucleated giant cells and endovascular trophoblasts. The role of Syncytin-1 in extravillous trophoblasts invading the maternal endometrium is not known. Extravillous trophoblasts are also giant polyploid cells, but this ploidy is thought to be the result of endoreplication rather than of cell-cell fusion. Syncytin-1 may also play a role in villous or extravillous trophoblast proliferation in the presence of TGF-beta1 or TGFbeta3, in mediating immune-tolerance through different mechanisms or in delayed syncytiotrophoblast apoptosis. |
Disease | |
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Figure 6: Syncytin-1 and hASCT2 localization in first trimester placental villi: Using specific antibodies, Syncytin-1 expression was mainly found located at the apical syncytiotrophoblast membrane, whereas hASCT2 receptor was expressed at the membrane of cytotrophoblastic cells underlying the syncytiotrophoblast. | |
Entity | Multiple sclerosis |
Note | MSRV, multiple sclerosis associated retrovirus, was found originally in retrovirus-like particles budding from leptomeningeal-cells from MS patients. MSRV is closely related to the HERV-W family and Syncytin-1. However, the sequencing of ERVWE1 envelopes confirmed that the MSRV envelope (GenBank accession no. AF331500) was not encoded by the ERVWE1 locus. As ERVWE1 is the only W-locus bearing a full-length envelope, it was proposed that MSRV particles may result either from transcomplementation of dispersed HERV-W copies simultaneously activated or from an as yet uncharacterised exogenous retrovirus. MSRV envelope has been proposed to exert various immune properties such as inducing immune response, triggering a superantigen effect, mediating cytokine production and activating innate immunity. |
Disease | Multiple sclerosis (MS) is a complex inflammatory, auto-immune and demyelinating disease. Syncytin-1 is expressed in specific types of cells in the brain regions affected by MS. These cell types are the astrocytes, glial cells and activated macrophages of MS lesions. Syncytin-1 expression in astrocytes mediates neuroimmune activation and death of oligodendrocytes by inducing the release of redox reactants, cytotoxic for oligodendrocytes. In astrocytes, Syncytin-1 induces the expression of OASIS (old astocytes specifically induced substance), an endoplasmic reticulum stress sensor, which in turn leads to increased expression of inducible NO synthase and concurrent suppression of hASCT1 in astrocytes, resulting in diminished myelin protein production. What mechanisms reactivate Syncytin-1 in the brain in MS is still not clear. It could be the result of viral infection of the brain, such as herpes simplex virus, which has previously been shown to transactivate Syncytin-1 expression, or cytokine deregulation. Indeed it has been shown in astrocyte cultures that MS detrimental cytokines, IFN-gamma and TNF-alpha are able to induce Syncytin-1 expression through NF-kappaB activation, while MS protective IFN-beta inhibits its expression. In addition Syncytin-1 induction by exogenous TNF-alpha into the corpus callosum, a region of the brain frequently exhibiting demyelination in MS, leads to neuroinflammation, diminished myelin proteins and neurobehavioural deficits in Syncytin-1-transgenic mice, as observed in MS. Moreover in turn, endogenous TNF-alpha and other inflammatory cytokines are induced. These observed inductions seems to occur specifically in astrocytes. Another study from the same group reported an increase in ERVWE1 DNA copy number, without evidence of new integration events or viral replication. Whether these sequences are episomal, result of endoreplication of part or the whole of chromosome 7 or belong to another retroviral sequence remains to be clarified. Expression of Syncytin-1, like of other members from the HERV-W and other HERV families, in the MS brain are not thought to be an aetiological factor but more a consequence of increased immune activity, but it now seems clear that Syncytin-1 may have an important role in the pathogenesis of MS. |
Prognosis | The presence of Syncytin-1 in MS may indicate a poor prognosis, as Syncytin-1 mediates the induction of redox reactants and causes oligodendrocyte death and demyelination. |
Entity | Other brain neuro-inflammatory diseases |
Note | HERV upregulation and their probable implication has been suggested in several other neurological disorders. However it has been shown that HERV-W env/ERVWE1 env mRNAs were not differentially regulated in schizophrenia and bipolar disorders compared with controls. |
Entity | Cancers |
Note | HERV expression/activation, including that of the HERV-W family seems to be a common feature in cancers, a phenomenon that has been linked to deregulation of methylation. However, whether they are triggers or markers of carcinogenesis has still not been elucidated. HERV-W env sequences have been detected by EST or RT-PCR in several cancers such as brain cancer, kidney cancer, ovary cancer and skin cancer and in various cancer cell lines (Table 1). Conversely, ERVWE1/Syncytin-1 mRNA has been found in 38% of breast cancer specimens and in all benign and malignant endometria with the highest expression in endometrial carcinoma (EnCa). In these cases Syncytin-1 protein was concurrently expressed and there is evidence of fusion between cancerous cells expressing Syncytin-1 and endothelial cells. in vitro studies showed the involvement of Syncytin-1 in the fusion process between breast cancer cell lines and endothelial cells, and in the fusion or the proliferation of EnCa. This last point is linked with cAMP-stimulated cell-cell fusion or hormone-induced cell proliferation. Indeed steroid hormones induce both Syncytin-1 and TGF-beta1 and TGF-beta3, and the latters operate a switch in Syncytin-1 function from fusion to cell differentiation. |
Prognosis | In breast cancers, the expression of Syncytin-1 may indicate a good prognosis, as suggested by one study. Indeed fusion between cancer and normal cells can either lead to restoration of the apoptosis cascade, or to cell differentiation, leading to a reduced tumorigenicity. However cancerous cells fusion may also lead on the contrary to a more aggressive phenotype, and, if fusion occurs with vascular endothelial cells, to metastasis. Furthermore, the cell proliferation and suggested anti-apoptotic capacities of Syncytin-1 are more characteristics of oncogenes. |
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Table1: HERV-W, ERVWE1 and Syncytin-1 expression: Detection of HERV-W env mRNA transcripts by Northern blot (NB), RT-PCR, real-time RT-PCR (Q-RT-PCR), or by analysis of Expressed Sequence Tag (ESTs) databases. Depending on the method used (e.g. primers within the env ORF, primers overlapping splice junction , ...), either only ERVWE1 specific transcripts are detected (labelled ERVWE1) or env-containing HERV-W transcripts are detected (labelled HERV-W). Relative expression of ERVWE1 transcripts in normal tissue is indicated in red (1,000-10,000), orange (10-100) and yellow (1-10). Whether ERVWE1 mRNA expression correlates with protein expression detected by immunocytochemistry (IM) or western blotting (WB) is indicated (glycoprotein detection is labelled Syncytin-1). Note that HERV-W mRNA expression does not preclude neither the presence nor the absence of ERVWE1 expression (labelled ERVWE1 and HERV-W when both are identified). | |
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Citation |
This paper should be referenced as such : |
Gimenez, J ; Mallet, F |
ERVWE1 (endogenous retroviral family W, Env(C7), member 1) |
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):134-148. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://AtlasGeneticsOncology.org/Genes/ERVWE1ID40497ch7q21.html |
Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ] |
t(7;14)(q21;q32) ERVW-1/IgH
t(7;14)(q21;q32) IGH/ERVW-1 |
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