Evidence for a Nonallelic Heterogeneity of Epidermodysplasia Verruciformis with Two Susceptibility Loci Mapped to Chromosome Regions 2p21–p24 and 17q25

Abstract

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.

Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: A case‐control study

“…This polymorphism is thought to be located in a putative transmembrane domain. 4 We have found that the presence of a polymorphism in the EVER2 gene is not only associated with the presence of HPV antibodies in control subjects but also an increased risk of squamous cell carcinoma of the skin. It is possible that EVER genes are involved in controlling the HPV pathogenesis in epidermal keratinocytes or that they directly affect the innate or adaptive immune responses which may control the clearance of EV-HPVinfected keratinocytes.…”

“…We have shown here that a very common single nucleotide polymorphism increases the likelihood for HPV seropositivity. Although the precise role of EVER2 is unknown, EVER2 transcript has been isolated from spleen and thymus tissue, as well as from normal skin, 4,16 supporting its hypothesized role in the immunogenic response.…”

“…The high amino acid conservation of 75-96% identity among human and mouse proteins 4,16 implies that mutations and polymorphisms that alter the coding sequence in the corresponding genes are subjected to significant selective pressure; thus advocating that TMC proteins have important cellular roles. The single nucleotide polymorphism studied here results in a change from the nonpolar isoleucine to the polar asparagine.…”

“…Furthermore, EV patients experience diminished cell-mediated immunity possibly resulting in an observed susceptibility to infection by specific HPV types falling into the genus b, with HPV5 and HPV8 the most prevalent infections in this patient population. 2 Genome-wide linkage studies were performed to map two EV loci 3,4 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.…”

Genetics of Epidermodysplasia Verruciformis

“…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].…”