Transmembrane channel-like protein 6 (TMC6, also known as EVER1) is a transmembrane protein consisting of 805 amino acids and is encoded by the gene TMC6 located on chromosome 17q25. TMC6 gene containing 19 exons encodes the EVER1/TMC6 protein which is predicted to possess 10 transmembrane domains and is localized in the endoplasmic reticulum. The germline mutation of the TMC6 gene is associated with epidermodysplasia verruciformis (EV), which is characterized by abnormal susceptibility to human papillomavirus (HPV) of the β genus, but is harmless to the general population. In addition to TMC6, mutations in TMC8/EVER2 protein encoded by TMC8 gene are also considered to be related to EV. TMC6and TMC8 are widely expressed throughout the body. The EVER1 or EVER2 deficiency in keratinocytes, which normally express both proteins and are the natural and exclusive host cells of β-HPVs, is considered to be the cellular basis of the disease.
|Basic Information of TMC6|
|Protein Name||Transmembrane channel-like protein 6|
|Aliases||Epidermodysplasia verruciformis protein 1, Protein LAK-4|
|Organism||Homo sapiens (Human)|
Epidermodysplasia verruciformis (EV) is a rare autosomal recessive disorder characterized by abnormal susceptibility to infection of cutaneous HPV of the β genus and an apparently increased risk of skin cancer. Recently, EV genes, EVER1/TMC6 and EVER2/TMC8, are identified and mutations of these genes are responsible for the development of EV disease. The TMC6/8 genes may be involved in controlling the expression and replication of HPV genes in epidermal keratinocytes, or they may directly affect innate and adaptive immune responses which control the clearance of HPV-infected keratinocytes in EV cases. Moreover, there is a correlation between genetic variation in the TMC6/8 region and persistent HPV infection as well as the risk of cervical cancer (CxCa). Numerous studies have demonstrated that single nucleotide polymorphisms (SNPs) in the TMC6 and TMC8 genomes are associated with CxCa susceptibility, but the specific mechanisms require further investigation. The link between the TMC6/8 genes and HPV susceptibility makes them interesting candidate genes in CxCa.
Fig.1 Summary of TMC6 mutations reported in EV. cDNA, complementary DNA; EV, epidermodysplasia verruciformis; IVS, intervening sequence. (Gober, 2006)
In this article, two new mutations of the EVER1/TMC6 gene in Japanese EV patients are identified by a polymerase chain reaction and DNA sequencing analysis.
This study does not find any associations with the EVER1/EVER2 (also known as transmembrane channel protein TMC6 and TMC8) SNPs and HPV status of mucosal HNSCC or between HNSCC patients and controls.
This article shows that the common genetic variation of TMC6/8 is not associated with squamous cell skin cancer (SCSC), but the three variants in TMC8 (rs12452890, rs412611 and rs7208422) are associated with a higher seroprevalence for beta papillomaviruses which may play a role in the excess risk of SCSC.
The data from this study support the theory that TMC6/8 is involved in cervical cancer susceptibility, but the results require further analysis and validation.
This article reports that EV-related proteins, EVER1 and EVER2 (now called TMC6 and TMC8) proteins are localized in the endoplasmic reticulum and have the characteristics of integrated membrane proteins, but the role of EVER protein in the development of persistent HPV infection remains to be discovered.
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