Focus of our research is understanding and addressing sporadic and hereditary inflammatory skin conditions, especially neutrophil-mediated inflammatory dermatoses (NMID). For that we use next-generation sequencing methods and CRISPR-Cas9 edited cell culture models.
Neutrophil-mediated inflammatory dermatoses (NMID)
Our main focus is investigating the genetic architecture of neutrophil-mediated inflammatory diseases where the disease pathophysiology is still not well known. Our current investigation focuses on pustular psoriasis, acneiform skin conditions, pyoderma gangrenosum, Sweet syndrome. Furthermore, we are also interested in inflammation-related diseases such as linear localized scleroderma and collaborate with internal medicine on primary immunodeficiencies. We utilize whole exome sequencing and bioinformatics analysis pipelines to detect potential disease driving genetic alterations that can be taken forward for functional analysis in our web-labs using models and analyses techniques, some of whom were developed in-house.
Biological function polarity prediction of missense variants (BioPol)
Various in silico bioinformatics tools like SIFT, PolyPhen2, CADD, Condel and many others have been developed to predict the pathogenicity of missene variants. However, none of existing tools can actually predict the biological consequences of the missense variants on the protein function. Our main focus is to develop a machine learning based classifier that can actually predict whether a pathogenic missense variant causes gain of function or loss of function (biological function polarity) at the protein level. The tool will be available under navarinilab.com/projects.
We focus our studies on two genodermatoses, epidermodysplasia verruciformis (EV) and ichthyosis with confetti (IWC), aiming to improve the knowledge on correlation of variation, inflammation, and development of skin cancer.
EV is a rare autosomal-recessive genodermatosis. Patients develop plane wart-like lesions and non-melanoma skin cancer (NMSC), mostly in UV-exposed skin. The phenotype is conditional on human beta-papillomavirus (beta-HPV) infections. EV is one of the first identified primary immunodeficiency and caused by bi-allelic mutations in either TMC6/EVER1, TMC8/EVER2 or CIB1 in majority of patients.
IWC is an autosomal dominant inherited genodermatoses with less than 60 described patients. IWC patients are born with an erythematous scaling skin. During childhood patients develop thousands of pale spots on their skin which look like normal skin. Patients with IWC carry a dominant-negative heterozygous deletion or insertion in the 3’-end of the keratin 10 (KRT10) or keratin 1 (KRT1) gene. Translation of the gene results in a changed C-terminus of the protein and subsequently in its nuclear accumulation instead of cytoplasmic localization. In epidermal keratinocytes of IWC patients, but not in the underlying dermis or in lymphocytes as we could show, lots of mitotic recombinations or gene conversions occur on chromosome 17q where the KRT10 gene is located. This leads to a loss of heterozygosity (LOH) of the variation without loss of copy number and results in keratinocytes expressing the wildtype KRT10 only. These cells present as pale spots on patients’ skin. In contrast to EV patients, patients with IWC are not excessively reported to develop NMSC, but single descriptions of early skin cancer development exist. Estimation of cancer risk of IWC patients is difficult since the disease is ultra-rare. Extended knowledge on disease pathomechanism including the chromosomal exchange and skin inflammation will help to estimate cancer risk of patients.