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The TMC genes encode a set of homologous transmembrane proteins whose functions are not well understood. Biallelic mutations in either TMC6 or TMC8 are detected in more than half of cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV). It is controversial whether EV induced by mutations in TMC6 or TMC8 originates from keratinocyte or lymphocyte defects. Quantification of TMC6 and TMC8 RNA levels in various organs revealed that lymphoid tissues have the highest levels of expression of both genes, and custom antibodies confirmed protein expression in mouse lymphocytes. To study the function of these proteins we generated mice with targeted deletion mutant alleles of Tmc6 or Tmc8. Either TMC6 or TMC8 deficiency induced a reduction in apparent molecular weight and/or amount of the other TMC molecule. Co-immunoprecipitation experiments indicated that TMC6 and TMC8 formed a protein complex in mouse and human T cells. MS and biochemical analysis demonstrated that TMC6 and TMC8 additionally interacted with the CIB1 protein to form TMC6-TMC8-CIB1 trimers. We demonstrated that TMC6 and TMC8 regulated CIB1 levels by protecting CIB1 from ubiquitination and proteasomal degradation. Reciprocally, CIB1 was needed for stabilizing TMC6 and TMC8 levels. These results suggest why inactivating mutations in any of the three human genes leads to similar clinical presentations. We also demonstrated that TMC6 and TMC8 levels are drastically lower and the proteins are less active in regulating CIB1 in keratinocytes than in T cells. Our study suggests that defects in lymphocytes may contribute to the etiology and pathogenesis of EV.

The vast majority of primary immunodeficiencies (PIDs) occur due to the defects in cells originating from hematopoietic stem cells, while in some PIDs, there are defects in various genes responsible for non-leucocyte immune response such as seen in epidermodysplasia verruciformis (EV). EV caused by the mutations in TMC6, TMC8, and CIB1 genes is called "typical." "Atypical" EV may develop in patients with primary immunodeficiencies originating from hematopoietic stem cells, which include severe T-cell failure, caused by inactivating biallelic mutations of STK4, RHOH, CORO1A, ITK, TPP2, DCLRE1C, LCK, RASGRP1, or DOCK8 genes. Here, we present a family with TMC8 gene mutation leading to disseminated epidermodysplasia verruciformis including laryngeal papilloma and recurrent cutaneous squamous cell carcinomas. Typical EV with impaired local, keratinocyte-intrinsic immune response should be considered when routine immunological examinations are normal in patients presenting with clinical signs of EV. Although it is not possible to prevent EV lesions, early and appropriate surveillance for malignancy is mandatory.

Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to human beta papillomavirus infections and a particular propensity to develop non-melanoma skin cancers (NMSCs). The majority of EV cases are caused by biallelic null variants in TMC6, TMC8, and CIB1. This study aimed to identify disease-causing variants in three Chinese families with EV and to elucidate their molecular pathogenesis.Methods: Genomic DNA from the probands of three EV families was analyzed by whole-exome sequencing (WES). cDNA sequencing was performed to investigate abnormal splicing of the variants. Quantitative RT-PCR (qRT-PCR) was conducted to quantify the mRNA expression of mutant TMC6 and TMC8.Results: Whole-exome sequencing identified two novel homozygous variants (c.2278-2A > G in TMC6 and c.559G > A in TMC8) in families 1 and 2, respectively. In family 3, WES revealed a recurrent and a novel compound heterozygous variant, c.559G > A and c.1389G > A, in TMC8. The c.2278-2A > G TMC6 variant led to the skipping of exon 19 and resulted in premature termination at codon 776. Subsequent qRT-PCR revealed that the aberrantly spliced transcript was partly degraded. Notably, the TMC8 c.559G > A variant created a novel acceptor splice site at c.561 and yielded three different aberrant transcripts. qRT-PCR revealed that most of the mutant transcripts were degraded via nonsense-mediated mRNA decay (NMD).Conclusion: We identified three novel disease-causing variants in TMC6 or TMC8 in three Chinese families with EV. The EV phenotypes of the three patients were due to a reduction in TMC6 or TMC8. Our findings expand the genetic causes of EV in the Chinese population.

Epidermodysplasia verruciformis is a rare genodermatosis associated with mutations in the EVER1/TMC6 and EVER2/TMC8 genes. The inheritance is considered to be autosomal recessive, but reports suggesting an autosomal dominant inheritance indicate disease genetic heterogeneity. Its onset occurs in early childhood and presents as a combination of pityriasis versicolor-like, flat wart-like and seborrheic keratosis-like lesions, with a potential for malignant transformation, mainly squamous cell carcinoma.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to infection with b-genotype human papillomavirus (HPV) and a particular propensity to develop cutaneous malignancies. Clinical manifestations include flat, scaly, reddish hypo- and hyperpigmented macules, verruca-like papillomatous lesions, seborrheic keratosis- like lesions, and pink-red pityriasis versicolor-like lesions1.

International audience; Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to β-HPVs of EV patients.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to cutaneous human beta-papillomavirus infections causing persistent flat warts or pityriasis versicolor–like lesions. This generalized verrucous skin disorder resembles generalized verrucosis, but these 2 conditions are distinguished by differences in clinical manifestation and the human papillomavirus types involved. A breakthrough in our understanding of EV was the discovery that homozygous inactivating mutations in TMC6 ( EVER1 ) and TMC8 ( EVER2 ) determine susceptibility to this disorder; however, they have not solved all EV cases fully. These deficiencies account for 75% of affected individuals, leaving a substantial number of patients without an underlying genetic cause. Recently, it has been revealed that mutations in additional genes ( RHOH , MST-1 , CORO1A , and IL-7 ) result in extensive human beta-papillomavirus replication and therefore manifest with an EV-like phenotype. The term "acquired EV" is used to describe an EV-like phenotype that develops in immunocompromised hosts, and the introduction of this entity further aggravates the confusion. Reevaluation of these entities is warranted. Here, we review the available data on this issue, provide up to date information on the major characteristics that differentiate between these seemingly clinically similar disorders, and highlight the different mechanisms involved in each disorder.

Epidermodysplasia verruciformis (EV) is an autosomal recessive genodermatosis characterized by susceptibility to beta-genus human papillomavirus (HPV) infection. Owing to TMC6/EVER1 and TMC8/EVER2 mutations that lead to abnormal transmembrane channels in the endoplasmic reticulum involved in immunological pathways, keratinocytes cannot combat infection from non-pathogenic HPV strains. Mutations involving RHOH, MST-1, CORO1A, and IL-7 have also been associated with EV in patients without TMC6 or TMC8 mutations. We highlight a 27-year-old man with multiple violaceous flat-topped papules with scale and irregular borders distributed on his chest, extremities, abdomen, and back. The striking physical examination and the subsequent biopsy findings of enlarged nests of cells in the granular and spinous layers with blue-gray cytoplasm and keratohyaline granules confirmed the diagnosis. We conclude with a brief discussion on the differential diagnosis, which includes confluent and reticulated papillomatosis, Darier disease, and disseminated superficial actinic porokeratosis.

Background Four patients from three Norwegian families presented with a common skin phenotype of warts, molluscum contagiosum, and dermatitis since early childhood, and various other immunological features. Warts are a common manifestation of human papilloma virus (HPV), but when they are overwhelming, disseminated and/or persistent, and presenting together with other immunological features, a primary immunodeficiency disease (PIDD) may be suspected. Methods and results The four patients were exome sequenced as part of a larger study for detecting genetic causes of primary immunodeficiencies. No disease‐causing variants were identified in known primary immunodeficiency genes or in other disease‐related OMIM genes. However, the same homozygous missense variant in CARMIL2 (also known as RLTPR) was identified in all four patients. In each family, the variant was located within a narrow region of homozygosity, representing a potential region of autozygosity. CARMIL2 is a protein of undetermined function. A role in T‐cell activation has been suggested and the mouse protein homolog (Rltpr) is essential for costimulation of T‐cell activation via CD28, and for the development of regulatory T cells. Immunophenotyping demonstrated reduced regulatory, CD4+ memory, and CD4+ follicular T cells in all four patients. In addition, they all seem to have a deficiency in IFN γ ‐synthesis in CD4+ T cells and NK cells. Conclusions We report a novel primary immunodeficiency, and a differential molecular diagnosis to CXCR4‐,DOCK8‐,GATA2‐,MAGT1‐,MCM4‐,STK4‐,RHOH‐,TMC6‐, and TMC8‐related diseases. The specific variant may represent a Norwegian founder variant segregating on a population‐specific haplotype.

There is a growing association of human papillomavirus (HPV) with some cases of mucosal squamous cell carcinoma of the head and neck (HNSCC), particularly of the oropharynx. Persistent oral HPV infection is believed to increase the likelihood of malignancy, and it is possible that host genetic factors can determine susceptibility to persistent HPV infection. Polymorphisms in the two EV genes (EVER1 and EVER2, also known as transmembrane channel protein (TMC) 6 and 8) have been identified as strong candidate genes, since a small number of critical mutations in these genes have been shown to cause profound and florid skin HPV infections, and some of them have been linked to susceptibility to cervical cancer. We sought to determine whether there was a difference in the frequency of single nucleotide polymorphisms (SNPs) in EVER1 (rs2613516, rs12449858) and EVER2 (rs7205422, rs12452890) between HNSCC patients with HPV-positive and HPV-negative tumors, and healthy controls. We used logistic regression to analyze SNPs in 219 patients with histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx, or larynx, and 321 healthy controls. We did not find any associations with the EVER1/EVER2 SNPs and HPV status or being a HNSCC case or a control. The present data do not provide evidence for a role of genetic variations in EVER1 or EVER2 for HPV status of mucosal HNSCC or between HNSCC patients and controls.

Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.

Background: Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancer, mainly cutaneous squamous cell carcinoma (cSCC). Two genes (TMC6/EVER1 and TMC8/EVER2), mutated in epidermodysplasia verruciformis (EV) patients with an increased risk of cSCC development, contain numerous single-nucleotide polymorphisms (SNPs). Aim: To evaluate the effect of SNPs in both TMC/EVER genes on the different susceptibilities of RTRs to cSCC. Method: We determined the occurrence of cSCC in 105 RTRs who were transplanted at least 7 years previously and investigated the frequency of 26 SNPs within both TMC/EVER genes in severely affected (n = 16) as well as in nonaffected RTRs (n = 25). Results: Our data did not indicate a significant association between any SNP genotype and risk of cSCC development in RTRs. Conclusion: To clarify the correlation between SNPs in both TMC genes and cSCC development in RTRs, integrated investigations of large cohorts including both RTRs and immunocompetent individuals with consideration of cSCC status, SNP genotype and human papillomavirus status might be necessary.

Background Epidermodysplasia verruciformis (EV) is a rare genodermatosis that causes disseminated eruptions of hypo- or hyperpigmented macules and wart-like papules that can coalesce and scale. It is uniquely characterized by an increased susceptibility to specific human papillomavirus (HPV) genotypes. Classically, EV is associated with mutations of the EVER1/TMC6 and EVER2/TMC8 genes. The term "acquired" epidermodysplasia verruciformis was coined to describe an EV-like syndrome that can develop in patients with a compromised immune system. Recent discoveries of other genes implicated in EV, including RHOH, MST-1, and CORO1A, have complicated the classification of EV and EV-like syndromes. Methods We review the available data on epidermodysplasia verruciformis in the literature in order to propose a new classification system to encompass current and future developments on EV and EV-like syndromes. Results We propose classifying EV into: (1) classic genetic EV, (2) non-classic genetic EV, and (3) acquired EV. Conclusion The proposed categorization scheme provides a simple and logical way to organize the different cases of EV that have been described in the literature. This system organizes EV by its cause, allowing for a better understanding of the disease and helps differentiate EV from other causes of generalized verrucosis.

Background Epidermodysplasia verruciformis (EV) is a genodermatosis leading to infections with cutaneous HPV, persistent plane warts and a high rate of non-melanoma skin cancer (NMSC). Biallelic loss-of-function mutations in TMC6 and TMC8 are known to be causative. Objective The aim of this study was to report EV-causing mutations in four patients with EV and to give an overview of all described EV patients. Patients and methods We investigated four patients with classical features of EV from two families. All patients were affected by plane warts with typical EV histology since early childhood and β-HPVs were detected on their skin. One patient had recurring cutaneous squamous cell carcinomas (cSCC) and carcinomas in situ (Bowen type). We sequenced both TMC6/8 for disease-causing mutations and quantified levels of gene expression. We also performed a systematic literature review to discuss these patients in the context of previously reported cases, mutations already identified, as well as HPV types. Results Three patients of one family carried a homozygous splice site mutation in TMC8 resulting in aberrantly spliced transcripts that were not degraded. By contrast, no TMC6/8 mutation was detected in the patient from the other family. A systematic literature review revealed 501 described EV patients. Around 40% of EV patients analysed for genetic alterations carried no mutation in TMC6/8. While β-HPVs were identified in the majority of cases, α-HPVs were detected in several individuals. Conclusion The relatively high proportion of EV patients without mutation in TMC6/8 indicates the existence of EV-causing mutations in additional, presently unknown gene(s). However, a homozygous TMC8 splice site mutation in our patients resulted in aberrant transcripts which cannot retain the healthy phenotype. The literature review revealed that HPV-5 is the most commonly identified HPV in EV patients, but HPV-3, HPV-14, and HPV-20 were unexpectedly identified more frequently than HPV-8. This article is protected by copyright. All rights reserved.

Squamous cell skin cancer (SCSC) disproportionately affects organ transplant recipients, and may be related to increased viral replication in the setting of immune suppression. We conducted a nested case–control study among transplant recipients to determine whether SCSC is associated with antibodies to cutaneous human papillomaviruses (HPV), to genes associated with a rare genetic susceptibility to HPV (TMC6/TMC8), or to human polyomaviruses (HPyV). Cases (n = 149) had histologically confirmed SCSC, and controls (n = 290) were individually matched to cases on time since transplant, type of transplant, gender, and race. All subjects had serum drawn immediately prior to transplant surgery. Antibodies to 25 cutaneous HPVs and six HPyVs were assayed by detection of binding to virus-like particles, and 11 TMC6/8 variants were genotyped. After correction for multiple comparisons, only antibodies to HPV37 were associated with SCSC (OR 2.0, 95% CI 1.2–3.4). Common genetic variants of TMC6/8 were not associated with SCSC, but three variants in TMC8 (rs12452890, rs412611, and rs7208422) were associated with greater seropositivity for species 2 betapapillomaviruses among controls. This study suggests that some betaHPVs, but not polyomaviruses, may play a role in the excess risk of SCSC among transplant recipients.

Cervical cancer is the forth most commonly diagnosed cancer among women worldwide. It is caused by persistent infection with an oncogenic type of Human Papillomavirus (HPV). The HPV is a necessary but not sufficient cause of cervical cancer. Environmental factors such as smoking, high parity and long-term use of oral contraceptives increases the risk of cervical cancer. Genetic factors also affect the risk of developing the disease. The aim of this thesis is to search for and evaluate genetic risk factors for cervical cancer using both a candidate gene approach and a genome-wide association study (GWAS). Paper I examined the association of genetic variation in three Fanconi Anemia (FA) genes (FANCA, FANCC and FANCL), involved in DNA repair, with cervical cancer susceptibility in the Swedish population. No association was observed. Paper II evaluated the association of genetic variation in the TMC6 and TMC8 genes with susceptibility to cervical cancer in the Swedish population and an association of two SNPs (rs2290907 and rs16970849) with cervical cancer was observed. In paper III the first GWAS performed in cervical cancer was reported. Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were found to affect the susceptibility to cervical cancer. Paper IV examined the sequence variation in the TMC6 and TMC8 region and its association with cervical cancer. A highly polymorphic 21 bp sequence was identified and found to be repeated 5 to 42 times in both cases and controls. Lack of this repeat was associated with increased risk of cervical cancer. An intronic SNP (rs2926778) located in between the TNRC6C and TMC6 genes was also found to be associated with cervical cancer. The thesis provides evidence for the importance of genes in the immune system for cervical cancer susceptibility. The genetic risk factors identified explain only a part of the genetic susceptibility, implying that other risk factors remains to be identified

Epidermodysplasia verruciformis (EV) is a rare autosomal recessive genodermatosis associated with a high risk of skin carcinoma. EV results from an abnormal susceptibility to infection by specific human papillomavirus (HPV) genotypes (beta-papillomaviruses) which include the potentially oncogenic HPV5. EV-specific HPVs are considered as harmless for the general population. EV was recently found to be caused by invalidating mutations in two adjacent, related, novel genes, EVER1/TMC6 and EVER2/TMC8. EVER genes encode transmembrane proteins located in the endoplasmic reticulum, which are likely to function as modifiers of ion transporters or channels and to be involved in signal transduction. It was proposed that EV was a primary defect of innate immunity. 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.

Epidermodysplasia verruciformis (EV) is a rare auto­ somal recessive disease characterised by abnormal susceptibility to disease-specific human papillomaviruses (HPVs), possibly due to suppressed cellular innate im­ munity. EVER1/TMC6 or EVER2/TMC8 gene mutations are often found in EV (1). All patients with EV usually have similar skin lesions from their childhood, involving disseminated flat warts or pityriasis versicolor. Elderly patients with EV have a high risk of developing carcino­ mas in situ and invasive squamous cell carcinoma (SCC) associated with HPV infections, mainly on sun­exposed skin. On the other hand, Merkel cell polyomavirus (MC­ PyV) is detected in most Merkel cell carcinomas (MCC) (2), which arise from Merkel cells, neuroendocrine cells in the skin. We present here a rare occurrence of MCPyV+ MCC in a patient with EV.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by increased sensitivity to infection by the β-subtype of human papillomaviruses (β-HPVs), causing persistent, tinea versicolor-like dermal lesions. In a majority of affected individuals, these macular lesions progress to invasive cutaneous squamous cell carcinoma (CSCC) in sun-exposed areas. While mutations in transmembrane channel-like 6 (TMC6 / EVER1) and 8 (TMC8 / EVER2) have been causally linked to EV, their molecular functions are unclear. It is likely that their protective effects involve regulation of the β-HPV life cycle, host keratinocyte apoptosis vs. survival balance and/or T-cell interaction with infected host cells.

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. EV is usually considered as an autosomal recessive condition. Taking EV as a model to identify a locus underlying the susceptibility to HPV infections, we performed a genome-wide search for linkage with 255 microsatellite genetic markers in three consanguineous EV families comprising six patients, using the homozygosity mapping approach. Homozygosity restricted to affected individuals was observed for a marker of chromosome 17q (D17S784) in two families and a marker about 17 centiMorgan (cM) distal (D17S1807) in the third family. Ten additional microsatellite markers spanning 29 cM in this region were analyzed. Two-point lod score values greater than 3 were obtained for four markers and multipoint linkage analysis yielded a maximum lod score of 10.17 between markers D17S939 and D17S802. Recombination events observed in two families allowed a candidate region for the EV susceptibility locus to be mapped to the 1 cM region defined by these two markers. The EV locus (named EV1) is included in the 17qter region recently found to contain a dominant locus for the susceptibility to familial psoriasis. It has been shown that patients suffering from psoriasis are likely to constitute the reservoir of HPV5. It is thus tempting to speculate that distinct defects affecting the same gene may be involved in the two skin conditions.

The initial link between HPV and skin cancers was a rare autosomal inherited disease called Epidermodysplasia Verruciformis (EV) first described nearly a century ago.1 The disease is characterized by cutaneous lesions that display a high rate of progression to squamous cell carcinomas (SCCs) beginning in the second decade of life. Furthermore, EV patients experience diminished cell-mediated immunity possibly resulting in an observed susceptibility to infection by specific HPV types falling into the genus β, with HPV5 and HPV8 the most prevalent infections in this patient population.2 Genome-wide linkage studies were performed to map two EV loci3,4 and to identify the EVER genes (EVER1 or EVER2, also referred to as TMC6 and TMC8, respectively) in one of these loci.5 The identification of EVER1 and EVER2 expressed sequence tags and cDNA from lymphoid tissue is consistent with a model in which EV mutations exert their direct effects in the immune system. It was recently discovered that 75% of EV patients studied have rare mutations in either of these adjacent, related, novel genes. To date, 10 truncating, loss of function mutations have been identified, 4 in EVER1 and 6 in EVER2 and were identified in EV patients from Algeria, Columbia, Poland and Japan.5 More recently, 5 additional mutations have been detected in the EVER genes supporting the hypothesis that EVER1 and EVER2 are the molecular basis of EV.6–8 β-HPV DNA has been detected in up to 50% of SCC tumors from immunocompetent individuals and in up to 90% of lesions from immunocompromised individuals,9,10 further emphasizing the role of host susceptibility in infection with these viruses. Recently, we reported that the presence of antibodies to viral proteins of HPV types in the genus β, particularly HPV5, was associated with risk of SCC.11 We hypothesize that a common nonsynonymous single nucleotide polymorphism in the EVER2 gene also may be related to infection with β-HPVs. Here we report that this particular SNP (rs7208422), located in the most highly conserved region of the gene, is not only associated with SCC of the skin but also with the presence of antibodies to genus β-HPVs in control subjects.

Epidermodysplasia verruciformis (EV; MIM#226400) is a genodermatosis characterized by susceptibility to epidermodysplasia verruciformis-human papillomavirus (EV-HPV) infections which leads to early development of disseminated pityriasis versicolor-like and flat wart-like lesions [1]. The disease was first described by Lewandowski and Lutz in [1]. Approximately half of all patients with EV will develop cutaneous malignancies, predominately Bowen’s type carcinoma in situ and invasive squamous cell carcinomas that occur mainly on sun-exposed areas in the fourth or fifth decade of life [2-4].Thus, EV is in essence a genetic cancer of viral origin, and could also be regarded as a model of cutaneous HPV oncogenesis [5, 6]. In general, EV shows an autosomal recessive pattern of inheritance [7]. The EV loci were mapped to chromosome 2p21-p24 (EV2) and 17q25 (EV1) [8], respectively. In the EV1 interval, 2 adjacent related genes, EVER1 and EVER2, were identified in 2002 [9]. EVER proteins are members of transmembrane channel-like (TMC) family. They are encoded by 8 genes (TMC1-8). EVER1 and EVER2 correspond to TMC6 and TMC8, respectively [10, 11]. Therefore the recent literature has focused on the mutation finding the culpable gene. Clinical and histologic findings, EV-HPV, cutaneous oncogenesis, and genetics will be briefly reviewed.

Germline mutations of the EVER1/TMC6 gene are associated with epidermodysplasia verruciformis (EV), which is characterized by an abnormal susceptibility to human papillomaviruses that were considered to be innocuous for the general population. 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. Direct sequence analyses resulted in the identification of two novel mutations. One nonsense mutation consisting of a (C>A) transversion at nucleotide 744 in exon 8 in one EVER1 allele resulted in the introduction of a premature termination codon (Y248X). Another mutation was identified in the splice acceptor site of intron 8 (892-2, IVS8-2, A>T) in another allele. This is the second report of EVER1/TMC6 mutations in EV.

Epidermodysplasia verruciformis (OMIM 226400) is a rare autosomal recessive genodermatosis associated with a high risk of skin carcinoma that results from an abnormal susceptibility to infection by specific human papillomaviruses (HPVs). We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17q25. Here we report the identification of nonsense mutations in two adjacent novel genes, EVER1 and EVER2, that are associated with the disease. The gene products EVER1 and EVER2 have features of integral membrane proteins and are localized in the endoplasmic reticulum.

Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. The present study is a targeted candidate gene follow-up based on: i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease Epidermodysplasia Verruciformis (EV), and ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and cervical cancer. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNP) harbouring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III (CINIII) or invasive cervical cancer (ICC) and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 (ORGGvsAA = 0.6, 95% CI: 0.3 - 0.9, p = 0.02) and rs16970849 (ORAGvsGG = 0.8, 95% CI: 0.66 - 0.98, p = 0.03). The present data supports the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.

Epidermodysplasia verruciformis (EV) is a rare, autosomal recessive genodermatosis associated with a high risk of skin carcinoma (MIM 226400). EV is characterized by the abnormal susceptibility of otherwise healthy patients to infection by specific, weakly virulent human papillomaviruses (HPVs), including the potentially oncogenic HPV-5. Inactivating mutations in either of the related EVER1/TMC6 and EVER2/TMC8 genes cause most EV cases. New insights in EV pathogenesis have been gained from the following recent observations: (1) EV-specific HPVs (betapapillomaviruses) are defective for an important growth-promoting function encoded by an E5/E8 gene present in other HPVs, and inactivation of EVER proteins may compensate for the missing viral function; (2) the transmembrane viral E5/E8 and cellular EVER proteins interact both with the zinc transporter ZnT1, and are likely to modulate zinc homeostasis. EV may thus represent a primary deficiency in intrinsic, constitutive immunity to betapapillomaviruses, or constitute a primary deficiency in innate immunity (or both). Keratinocytes, the home cells of HPVs, are likely to play a central role in both cases. An important issue is to establish which cellular genes involved in intrinsic and innate antiviral responses play a part in the outcome of infections with other HPV types, such as genital oncogenic HPVs.

Summary Objective Epidermodysplasia verruciformis is a skin disease characterized by abnormal susceptibility to human papilloma viruses. Recently four mutations in the Epidermodysplasia verruciformis 1 gene ( EVER1 , also known as TMC6 ) have been associated with the disease. Because of the phenotypic similarity between Epidermodysplasia verruciformis and recurrent respiratory papillomatosis, we decided to investigate whether any of these mutations accounts for the susceptibility to human papilloma viruses in subjects with recurrent respiratory papillomatosis (RRP). Methods Allele-specific PCR and restriction fragment length polymorphisms (RFLPs) were employed for genotyping a cohort of 101 patients with recurrent respiratory papillomatosis. Results None of these four mutations were found in the studied subjects. Conclusion The absence of these mutations in RRP patients might indicate that EVER 1 alleles are not associated with susceptibility to RRP, or that other, as yet unidentified, mutations in the Epidermodysplasia verruciformis 1 gene, might account for the susceptibility to RRP.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by increased sensitivity to infection by the β-subtype of human papillomaviruses (β-HPVs), causing persistent, tinea versicolor-like dermal lesions. In a majority of affected individuals, these macular lesions progress to invasive cutaneous squamous cell carcinoma (CSCC) in sun-exposed areas. While mutations in transmembrane channel-like 6 (TMC6 / EVER1) and 8 (TMC8 / EVER2) have been causally linked to EV, their molecular functions are unclear. It is likely that their protective effects involve regulation of the β-HPV life cycle, host keratinocyte apoptosis vs. survival balance and/or T-cell interaction with infected host cells.

Epidermodysplasia verruciformis is a rare genodermatosis associated with a high risk of skin cancer. This condition is characterized by an abnormal susceptibility to specific related human papillomavirus genotypes, including the oncogenic HPV5. Epidermodysplasia verruciformis is usually considered as an autosomal recessive disease. We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17qter within the 1 cM interval between markers D17S939 and D17S802. 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. Using homozygosity mapping, linkage with 17qter markers was observed for family C2 only. Multipoint linkage analysis yielded maximum multipoint LOD-score values above 10 between markers D17S1839 and D17S802 encompassing the EV1 locus. A genome-wide search performed in family F1 yielded evidence for linkage between epidermodysplasia verruciformis and the chromosomal 2p marker D2S365. Nine additional microsatellite markers spanning 15 cM in this region were analyzed. Assuming an autosomal recessive inheritance with a complete penetrance, the expected maximum two-point LOD-score value of 1.8 was obtained for three markers and multipoint linkage analysis yielded a maximum LOD-score value of 3. 51 between markers D2S2144 and D2S392. 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. In contrast, linkage with 2p markers was excluded for family C2 and for the three families in which we mapped EV1 previously. The disclosure of two susceptibility loci for epidermodysplasia verruciformis provides evidence for a nonallelic heterogeneity in this disease.

† We describe a family with typical epidermodysplasia verruciformis (EV) in which only male members are affected. Whereas none of the index patient's ten children have EV, four of eight grandsons born to his daughters have inherited the disorder. All are infected with human papillomavirus (HPV) 3 and HPV 8. The inheritance in this kindred most likely results from an X-linked recessive genetic defect. Since other kindreds have been described with autosomal inheritance, this novel inheritance pattern suggests that the persistent high clinical susceptibility to HPV infection characteristic of EV may result from defects in either of at least two different genetic loci, one of which may be located on the X chromosome. (Arch Dermatol1985;121:864-868)