Predisposition to papillomaviruses epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is characterized by selective susceptibility to infections caused by skin-tropic oncogenic papillomaviruses (HPVs) of the B1 group, leading to an increase in the risk of epithelial skin cancer. It was first described clinically in 1922 (Jablonska & Majewski 1994). Autosomal recessive mutations in two adjacent genes, EVER1 and EVER2, were described in 2002 in three and two kindreds, respectively (Ramoz et al 2002). One patient with compound heterozygous mutations in EVER1 and another with a homozygous mutation in EVER2 were recently described (Tate et al 2004, Sun et al 2005). EVER genes belong to the transmembrane channel-like (TMC) family of genes, encoding proteins with eight membrane-spanning domains, thought to act as ion channels, transporters, or their associated modifiers (Kurima et al 2003, Keresztes et al 2003). The TMC family was first discovered by positional cloning of human inherited deafness (Kurima et al 2002). EVER1/TMC6 and EVER2/TMC8 are normally expressed in the endoplasmic reticulum of keratinocytes (Ramoz et al 2002). Despite recent progress, many questions about the function of EVER1/ TMC6 and EVER2/TMC8 and the role of their mutant alleles in the pathogenesis of EV remain unresolved. Patients with severe combined immunodeficiency (SCID) caused by yc and JAK3 deficiencies, but not SCID patients bearing other molecular defects, were recently shown to develop an EV-like clinical syndrome, despite successful haematopoietic stem cell transplantation (Laffort et al 2004). This probably reflects impaired expression of the two genes in keratinocytes, and possibly the impaired binding of their products with those of EVER1 and EVER2 (Laffort et al 2004). The in vitro) study of these genes in keratinocytes and the identification of new genetic aetiologies of EV should provide insight into protective immunity to papillomaviruses and the pathogenesis of papilloma-virus diseases in selected patients.

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