Human genetic and immunological dissection of epidermodysplasia verruciformis and related infections by skin-tropic, oncogenic beta-papillomaviruses
Final Report Abstract
Human b-papillomaviruses (b-HPV) generally cause asymptomatic infections. However, rare Mendelian predisposition to persistent b-HPV-induced skin lesions and non-melanoma skin cancer (NMSC) results in a primary immunodeficiency known as epidermodysplasia verruciformis (EV). EV has been considered a model disease to study b-HPV-induced pathogenesis and NMSC. Roughly 75% of EV cases are accounted for by loss-of-function mutations in EVER1/TMC6 and EVER2/TMC8. Although EVER1/2-defects are believed to impact keratinocyte-intrinsic HPV immunity, the cellular and molecular pathogenesis of EV and NMSC progression remain largely elusive. We hypothesized that novel gene defects could account for EV in patients with intact EVER1/2 genes and that identification of these defects could yield insight into the disease-causing mechanisms. Combining genome-wide-linkage analysis and whole-exome sequencing in 18 EV patients from 5 unrelated families of diverse ethnic origin (Colombia, France, Switzerland, Togo), we identified homozygous frameshift and non-sense variations in the gene CIB1. The mutant alleles segregate with EV as an autosomal recessive trait and shows complete clinical penetrance. CIB1 is a pleiotropic regulator of cellular signal transduction but has not been linked to antiviral immunity or keratinocyte function. The identified mutations lead to a complete loss of endogenous CIB1 protein expression in patient-derived B cells, keratinocytes and PBMC. Interestingly, CIB1 protein expression is strongly reduced in EVER1- and EVER2-deficient patient-derived cell lines, potentially linking CIB1 with EVER1/2. Of note, CIB1 protein stability is maintained by formation of a complex with EVER1/2 as identified by immunoprecipitation. While, CIB1-deficient patients show completely normal immune cell counts and function in healthy individuals CIB1 is highly expressed at barrier surfaces in the skin (epidermis and hair shaft). In cultured primary keratinocytes CIB1 seems to control proper formation of focal adhesions and coordination of cell migration on fibronectin substrates. We therefore propose that the CIB1:EVER1/2 complex controls an axis of keratinocyte-intrinsic immunity to b-HPV infection. Further characterization of CIB1- and EVER1/2-deficiency shall enable a better understanding of immunity against b-HPV, EV pathogenesis and NMSC progression.
Publications
- “The human gene damage index as a gene-level approach to prioritizing exome variants” Proc Natl Acad Sci. 2015 November 3; 112 (44): 13615-13620
Itan Y, Boisson B, Shang L, Patin E, Bolze A, Moncada-Vélez M, Scott E, Ciancanelli M, Lafaille F, Markle J, Martinez-Barricarte R, de Jong SJ, Kong X-F, Nitschke P, Belkadi A, Bustamante J, Puel A, Boisson-Dupuis S, Stenson PD, Gleeson JG, Cooper DN, Quintana- Murci L, Claverie J-M, Zhang SY, Abel L and Casanova J-L
(See online at https://doi.org/10.1073/pnas.1518646112)
