Disease relevance of TMC6

• Characterization of the transmembrane channel-like (TMC) gene family: functional clues from hearing loss and epidermodysplasia verruciformis [1].
• Epidermodysplasia verruciformis is a rare genodermatosis associated with a high risk of skin cancer [2].
• Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by an abnormal susceptibility to infection with a specific group of related human papillomavirus (HPV) genotypes, including the oncogenic HPV5 associated with the skin carcinomas developing in about half of EV patients [3].
• The EV locus (named EV1) is included in the 17qter region recently found to contain a dominant locus for the susceptibility to familial psoriasis [3].
• Specific DNA sequences from human papillomavirus have recently been detected in carcinomas from epidermodysplasia verruciformis patients, and in vulvar and cervical carcinomas but the role of papilloma viruses in the aetiology of these tumours is unclear [4].

Psychiatry related information on TMC6

• CONCLUSIONS: Epidermodysplasia verruciformis is a model not only of cutaneous viral oncogenesis but also of local defense mechanisms in the progression of human papillomavirus-associated cancers [5].
• Successively younger birth cohorts displayed an increase in prevalence and a decrease in onset-age for all disorders. "Ever" use of mental health services was higher for women with 3 or more comorbid disorders (65%) than for those with no disorder (9.8%), or only 1 disorder (51.4%) [6].
• RESULTS: Ever smoking a cigarette at baseline had a statistically significant impact on high depressive symptoms at follow-up [7].

High impact information on TMC6

• The gene products EVER1 and EVER2 have features of integral membrane proteins and are localized in the endoplasmic reticulum [8].
• We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17q25 [8].
• Oral retinoid treatment of human papillomavirus type 5-induced epidermodysplasia verruciformis [9].
• RESULTS: Ever having breast-fed was found to be associated with a 21% reduction in risk of childhood acute leukemias (odds ratio [OR] for all types combined = 0.79; 95% confidence interval [CI] = 0.70-0.91) [10].
• RESULTS: Ever use of ERT was associated with significantly decreased risk of fatal colon cancer (RR = 0.71; 95% confidence interval [CI] = 0.61-0.83) [11].

Chemical compound and disease context of TMC6

• Cryo-electron microscopy revealed that the functional domain (alpha(2)I) of human alpha(2)beta(1) integrin binds to a surface depression on the EV1 capsid [12].
• EV1 binding onto the cell surface and subsequent entry resulted in conformational changes of the viral capsid as demonstrated by sucrose gradient sedimentation analysis [13].
• Phylogenetic analyses of regions within LTR, reverse transcriptase, and env grouped the four virus strains together and similar to the maedi-visna OvLV strains, including visna virus, South African ovine maedi visna virus, and EV1 (British OvLV isolate), but they were distinct from caprine arthritis encephalitis virus [14].
• Two types of DNAs were clonally purified from the virion fraction which was obtained by the cesium chloride density gradient centrifugation of a homogenate of scrapings from benign lesions of typical epidermodysplasia verruciformis [15].
• Epidermodysplasia verruciformis with multiple mucosal carcinomas treated with pegylated interferon alfa and acitretin [16].

Biological context of TMC6

• EV results from an abnormal susceptibility to infection by specific human papillomavirus (HPV) genotypes (beta-papillomaviruses) which include the potentially oncogenic HPV5 [17].
• It was proposed that EV was a primary defect of innate immunity [17].
• Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses [17].
• Haplotype analysis allowed to map a candidate region for a second epidermodysplasia verruciformis susceptibility locus (EV2) within the 8 cM interval between markers D2S171 and D2S2347 of the 2p21-p24 region [2].
• We report here the genotyping for 10 microsatellite markers spanning 29 cM around EV1 in two consanguineous epidermodysplasia verruciformis families from Colombia (C2) and France (F1) comprising five patients and two patients, respectively [2].

Anatomical context of TMC6

• Our hypothesis is that EVER proteins act as restriction factors for EV-specific HPVs in keratinocytes, and that EV represents a primary deficiency of intrinsic immunity against certain papillomaviruses [17].
• In addition to natural ligands human echovirus-1 (EV1) gains entry into the cell by binding to alpha 2 beta 1 and taking advantage of alpha 2 beta 1 internalization via caveolae [18].
• Transient expression assays with keratinocytes and fibroblasts of epidermodysplasia verruciformis patients and controls demonstrated that the NRE activity is not cell specific [19].
• Epidermodysplasia verruciformis T cells were inhibited in their capacity to respond to allogeneic epidermal cells when they were simultaneously exposed to autologous epidermal cells from HPV-infected lesional epidermis, but not to normal-appearing epidermis [20].
• In view of the rare incidence of EV, we had a unique opportunity to perform a virologic study of the amniotic fluid and placenta from an EV patient infected with HPV5, HPV8, several other EV HPV, and HPV3 [21].

Associations of TMC6 with chemical compounds

• In contrast, linkage with 2p markers was excluded for family C2 and for the three families in which we mapped EV1 previously [2].
• The model indicates that alpha(2)beta(1) integrin cannot simultaneously bind both EV1 and the physiological ligand collagen [12].
• Two of us took 10 capsules or tablets of Dream Shape or Ever Youth, and changes in thyroid hormone levels were observed during the first 24 hours [22].
• Treatment of epidermodysplasia verruciformis with a combination of acitretin and interferon alfa-2a [23].
• Cimetidine therapy for epidermodysplasia verruciformis [24].

Other interactions of TMC6

• Here we report the identification of nonsense mutations in two adjacent novel genes, EVER1 and EVER2, that are associated with the disease [8].
• A susceptibility locus for epidermodysplasia verruciformis, an abnormal predisposition to infection with the oncogenic human papillomavirus type 5, maps to chromosome 17qter in a region containing a psoriasis locus [3].
• In this study, we have employed polymerase chain reaction and DNA sequencing analysis to characterize the EVER1 gene in a 65-year-old Japanese EV patient [25].
• A similar prevalence (56%) of TP53 mutations was found in 18 squamous cell carcinoma cases positive for epidermodysplasia verruciformis human papillomavirus types [26].
• TGF beta-1 and TNF alpha expression in the epidermis of patients with epidermodysplasia verruciformis [27].

Analytical, diagnostic and therapeutic context of TMC6

• METHODS: PCR and direct sequencing of the EVER1 and EVER2 genes were used to identify and confirm the mutations in our probands in the two families [28].
• Antisera prepared in rabbits against the 3 HPV pools coated and aggregated HPV in immune electron microscopy (IEM) tests but did not react with EV virions [29].
• A renal allograft recipient with an epidermodysplasia-verruciformis-like syndrome was found to have human papillomavirus type 5 (HPV-5) in his benign warty lesions and HPV-5 DNA in two of his skin cancers [30].
• DNA extracted from squamous cell carcinomas from patients with the chronic wart disease syndrome, epidermodysplasia verruciformis, was analyzed for the presence of human papillomavirus (HPV)-specific DNA sequences by Southern blot hybridization analysis [31].
• Skin autografts in epidermodysplasia verruciformis: human papillomavirus-associated cutaneous changes need over 20 years for malignant conversion [32].

References