Epidermodysplasia verruciformis (EV) is a congenital dermatosis characterized by lifelong disseminated and persistent flat wart lesions caused by beta-papillomaviruses (EV-HPVs). EV is associated with an increase in the risk of non-melanoma skin carcinomas (NMSC), but there are no other clinical signs in most patients (""""""""typical"""""""" EV). Morbid mutations in EVER1 and EVER2 were found in 2002. These proteins are expressed in T lymphocytes, which are involved in the clearance of HPV-infected epithelial cells, and in keratinocytes, the specific target cells of EV-HPVs. EVER proteins form a complex with the zinc transporter ZnT1 to regulate the intracellular Zn distribution and to control Zn-dependent transcriptional activity. The lack of pronounced T cell phenotype and T cell-related infections in these patients suggests that the mechanisms by which EVER deficiency confers susceptibility to EV-HPVs involves keratinocytes. EVER deficiencies account for approximately 75% of reported typical EV cases. We have recently identified AR RHOH and MST1 deficiencies in patients with EV and other clinical features (""""""""atypical"""""""" EV) due to a profound T cell deficiency. These discoveries showed that a T-cell defect can underlie persistent EV-HPV infections. In order to better understand the pathogenesis of EV, and to decipher the molecular and cellular mechanisms of immunity against EV-HPVs, we aim to identify novel genetic etiologies of EV using a hypothesis-free, genome-wide (GW) screening approach combining GW linkage (GWL) and whole-exome sequencing (WES). In our cohort of 15 kindreds, we obtained strong preliminary evidence of a novel EV-causing gene, with the identification of homozygous mutations in CIB1 in 6 patients from two Colombian kindreds and in one French patient. In these patients'EBV-B cell lines, there is a loss of expression of the calcium and integrin binding protein 1 (CIB1) protein. The CIB1-deficient patients display a typical form of EV. Our findings are therefore surprising, as CIB1 is ubiquitously expressed and none of its numerous known functions is connected with immunity against EV- HPVs. Mice lacking CIB1 display impaired thrombosis, angiogenesis, and spermatogenesis. We hypothesize that CIB1 deficiency impairs keratinocyte intrinsic immunity against EV-HPV. We intend to test the expression and function of CIB1 in both keratinocytes and T cells from healthy controls and CIB1-deficient patients. We will also explore a potential connection between CIB1 and EVER. Finally, we will study the growth of EV-HPV in control and patients'keratinocytes. The project is highly innovative yet perfectly feasible, and already supported by strong preliminary evidence. From a basic biological standpoint, this research will provide considerable insight into the mechanisms of immunity against EV-HPV, notably by clarifying the role of CIB1 in keratinocytes, thereby possibly defining the cellular basis of EV. From a clinical standpoint, the dissection of the pathogenesis of EV will provide molecular diagnoses for patients and genetic counseling for families and will pave the way for the study of other HPV-driven pathologies.
The four known genetic etiologies of typical or atypical epidermodysplasia verruciformis (EV), with loss-of- function bi-allelic mutations in EVER1, EVER2, RHOH and MST1, suggest that both keratinocytes and T cells contribute to protective immunity against EV-causing human papillomaviruses (EV-HPVs). We hypothesize that typical and atypical EV in other patients result from novel single-gene inborn errors of immunity. We aim to decipher novel genetic etiologies of EV following hypothesis-free, genome-wide approaches, which may reveal new aspects of the molecular and cellular mechanisms underlying cutaneous immunity against EV-HPVs.
|Scott, Eric M; Halees, Anason; Itan, Yuval et al. (2016) Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet 48:1071-6|