TMC6

Abstract: 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.

Abstract: † 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)

Abstract: 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.