TMC and EVER genes belong to a larger novel family, the TMC gene family encoding transmembrane proteins

Keresztes, Gábor; Mutai, Hideki; Heller, Stefan

doi:10.1186/1471-2164-4-24

Cited by 137 publications

(116 citation statements)

References 14 publications

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“…This predicted topologic structure resembles that of Shaker K + and TRP channels [19,21] (Fig. 4), suggesting that TMC1 may function as a receptor, pump, transporter, channel, or modifiers of such proteins [19,21,20,15]. This topologic organization of TMC1 has been experimentally confirmed for mouse TMC1 expressed in heterologous systems [21].…”

Section: Introductionmentioning

confidence: 61%

Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation

Kawashima

Kurima

Pan

et al. 2014

Pflugers Arch - Eur J Physiol

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Mutations of the transmembrane channel-like 1 (TMC1) gene can cause dominant and recessive forms of deafness in humans and mice. TMC1 is one of eight mammalian TMC genes of unknown function. The multi-pass transmembrane topologic structure of the proteins they encode suggests roles as a receptor, transporter, channel or pump. Tmc1 and the closely related Tmc2 gene are expressed in neurosensory hair cells of the auditory and vestibular end organs of the mouse inner ear. Recent studies have demonstrated that Tmc1 and Tmc2 are specifically required for mechanoelectrical transduction in hair cells. The exact role of these proteins in mechanoelectrical transduction is unknown. TMC1 and TMC2 are viable candidates for the mechanoelectrical transduction channel of hair cells, whose component molecules have eluded identification for over 30 years. We expect that studies of TMC proteins will yield insights into molecular components and mechanisms of mechanosensation in auditory and vestibular hair cells, as well as in other tissues and organs.

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Section: Introductionmentioning

confidence: 61%

Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation

Kawashima

Kurima

Pan

et al. 2014

Pflugers Arch - Eur J Physiol

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“…Upregulation of both genes was observed also in NIKS transfected with a plasmid containing the green fluorescent protein (GFP) gene (data not shown), suggesting that EVER1 and EVER2 expression could be activated when cells are exposed to exogenous DNA. To corroborate our data, we repeated the experiments in B lymphocytes, which are known to express very high levels of EVER1 and EVER2 (6,8,9). Myeloma-derived RPMI-8226 cells were transfected with the bacterial plasmid pBluescript SK (pBSK), which due to the absence of eukaryotic promoters in its sequence, does not produce any transcript in mammalian cells.…”

mentioning

confidence: 99%

“…These new data justify further investigations to evaluate whether EVER protein functions are relevant in other cells and/or are linked with infection with pathogens other than beta HPVs. Interestingly, human lymphocyte populations (6) and, in particular, human B cells, are among the cells carrying the highest levels of EVER1 and EVER2 genes (8).…”

mentioning

confidence: 99%

Expression of the Epidermodysplasia Verruciformis-Associated Genes EVER1 and EVER2 Is Activated by Exogenous DNA and Inhibited by LMP1 Oncoprotein from Epstein-Barr Virus

Frecha

Chevalier

Uden

et al. 2015

J Virol

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dEVER1 and EVER2 are mutated in epidermodysplasia verruciformis patients, who are susceptible to human betapapillomavirus (HPV) infection. It is unknown whether their products control the infection of other viruses. Here, we show that the expression of both genes in B cells is activated immediately after Epstein-Barr virus (EBV) infection, whereas at later stages, it is strongly repressed via activation of the NF-B signaling pathway by latent membrane protein 1 (LMP1). Ectopic expression of EVER1 impairs the ability of EBV to infect B cells. E pidermodysplasia verruciformis (EV) is a rare primary immunodeficiency, and EV patients have an increased susceptibility to infection with human betapapillomaviruses (beta HPVs) (1, 2). The familial occurrence of the disease led to the search for an EV gene involved in the control of HPV infection. In 2002, Ramoz et al. described that mutations in two adjacent novel genes called EVER1 (TMC6) and EVER2 (TMC8) are considered the two genetic etiologies of EV (3-5). Until now, the role of the two proteins EVER1 and -2 has been exclusively circumscribed to keratinocytes, in which they control the intracellular levels of zinc (2). However, in a recent report a link between EVER proteins and intracellular zinc homeostasis was documented in T cells from an EVER-deficient patient (6). In addition, peripheral blood T cells of EV patients showed a biased memory/naive T cell ratio and increased skin homing surface markers, although no alteration in cell proliferation was observed (7). These new data justify further investigations to evaluate whether EVER protein functions are relevant in other cells and/or are linked with infection with pathogens other than beta HPVs. Interestingly, human lymphocyte populations (6) and, in particular, human B cells, are among the cells carrying the highest levels of EVER1 and EVER2 genes (8).We first evaluated whether these genes play a role at an early stage of HPV infection and transiently transfected spontaneously immortalized keratinocytes (NIKS) with a linearized 8-kb fragment of the beta HPV38 genome. EVER1 and EVER2 mRNA levels were increased 24 h posttransfection (Fig. 1A). Upregulation of both genes was observed also in NIKS transfected with a plasmid containing the green fluorescent protein (GFP) gene (data not shown), suggesting that EVER1 and EVER2 expression could be activated when cells are exposed to exogenous DNA. To corroborate our data, we repeated the experiments in B lymphocytes, which are known to express very high levels of EVER1 and EVER2 (6,8,9). Myeloma-derived RPMI-8226 cells were transfected with the bacterial plasmid pBluescript SK (pBSK), which due to the absence of eukaryotic promoters in its sequence, does not produce any transcript in mammalian cells. pBSK transfection into RPMI-8226 cells resulted in a rapid increase in EVER1 and EVER2 mRNA levels that persisted up to 48 h posttransfection (Fig. 1B). In addition, exposure of the same cells to the Toll-like receptor 3 (TLR3) ligand polyinosinic poly(C) [poly(I·C)], whic...

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“…TMC genes encode integral membrane proteins that localise to the endoplasmic reticulum and are predicted to form transmembrane channels. The exact function of these proteins is still unclear, but it is assumed that they belong to a new group of channels or ion transporters and could be involved in signal transduction [7,8]. EVER1/TMC6 and EVER2/TMC8 act as modifiers of zinc transporter ZnT-1.…”

Section: Discussionmentioning

confidence: 99%

“…EVER proteins are members of the transmembrane channel-like (TMC) family. They are encoded by 8 genes (TMC1–8) [7,8]. EVER1 and EVER2 correspond to TMC6 and TMC8, respectively.…”

Section: Introductionmentioning

confidence: 99%

Homozygosity for the c.917A → T (p.N306l) Polymorphism in the EVER2/TMC8 Gene of Two Sisters with Epidermodysplasia Verruciformis Lewandowsky-Lutz Originally Described by Wilhelm Lutz

et al. 2010

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Background: Epidermodysplasia verruciformis Lewandowsky-Lutz (EV) is a rare genodermatosis, characterised by development of numerous verrucous skin lesions caused by specific genotypes of human papillomaviruses belonging to the β-papillomavirus genus. The EV loci were mapped to chromosome 2p21–p24 (EV2) and 17q25 (EV1). On chromosome 17, 2 adjacent related genes – EVER1/TMC6 and EVER2/TMC8 – were identified. We reinvestigated 2 patients originally described by Wilhelm Lutz in 1946 with the aim to document the natural course of the disease and confirm his diagnosis. Methods: PCR fragments specific for exons with short flanking intron sequences of EVER1/TMC6 and EVER2/TMC8 genes from patients’ DNA were amplified using sequence information. The single-nucleotide polymorphism (SNP) rs7208422 was studied, using restriction fragment length polymorphism analysis. Results: In the index patient, we identified a homozygous TT genotype in exon 8 of the EVER2/TMC8 gene (c.917A → T, p.N306I). The same mutation could thereafter be detected in her sister from paraffin-embedded skin. Conclusion: We have followed one of the first patients described with EV in Basel, Switzerland, in 1930 until today and demonstrated the TT genotype (SNP rs7208422) in the EVER2/TMC8 gene in this index patient and her sister. The results underline the possible relevance of SNP rs7208422 by influencing the susceptibility to β-papillomaviruses and their oncogenic potential.

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TMC and EVER genes belong to a larger novel family, the TMC gene family encoding transmembrane proteins

Cited by 137 publications

References 14 publications

Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation

Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation

Expression of the Epidermodysplasia Verruciformis-Associated Genes EVER1 and EVER2 Is Activated by Exogenous DNA and Inhibited by LMP1 Oncoprotein from Epstein-Barr Virus

Homozygosity for the c.917A → T (p.N306l) Polymorphism in the EVER2/TMC8 Gene of Two Sisters with Epidermodysplasia Verruciformis Lewandowsky-Lutz Originally Described by Wilhelm Lutz

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