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Introduction and aims Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultrarare genodermatosis associated with a homozygous pathogenic variant, c.-95delC in POMP, which encodes for proteasome maturation protein. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. The pathophysiology of KLICK syndrome is poorly understood, resulting in nonspecific, limited treatment options. The aim of this work is to characterize KLICK syndrome at the cellular and molecular level, with the utilization of transcriptomic techniques for potential drug repurposing. Methods A lesional skin biopsy was obtained, following informed consent, from a 32-year-old female patient with KLICK syndrome. Histology and immunostaining were used to characterize the disrupted skin architecture. RNA sequencing was used to identify key dysregulated pathways and the L1000FWD reverse transcriptomics tool enabled the generation of a shortlist of potential therapeutics for KLICK syndrome. CRISPR editing techniques and induced pluripotent stem cell (iPSC) reprogramming Methods were used to generate cellular based models carrying the pathogenic POMP variant in order to support evaluation of the shortlisted therapeutic options. Results KLICK syndrome skin histology featured hyperkeratosis, hypergranulosis and delayed cellular flattening. Consistent with pathological features, pathway analysis of transcriptomic data revealed keratinocyte differentiation and epidermis development as key upregulated pathways in KLICK syndrome. Interestingly, the Panther pathway analysis tool suggested dysregulation in epidermal growth factor receptor (EGFR) signalling, and reverse transcriptomics identified erlotinib, an EGFR inhibitor, as a potential therapeutic treatment for KLICK syndrome. HaCaT keratinocytes were successfully edited using CRISPR-Cas9 to carry the KLICK patient POMP variant and a KLICK patient iPSC line was generated to support in vitro KLICK syndrome modelling. Conclusions KLICK syndrome is a hyperproliferative inflammatory skin disorder associated with a pathogenic variant in POMP. Reverse transcriptomics is a useful tool for shortlisting drugs with biologically relevant mechanisms of action with potential for treatment of rare genetic diseases such as KLICK syndrome. [ABSTRACT FROM AUTHOR]

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is an ultra-rare genodermatosis. Clinical manifestations include linear hyperkeratotic papules in the flexures, palmoplantar keratoderma and pseudoainhum. To date, all affected individuals carry a homozygous pathogenic variant, c.-95delC in POMP , which encodes for proteasome maturation protein. Disease pathophysiology is not well understood, resulting in nonspecific and limited treatment options. However, clinically, the phenotype shows erythema and inflammation, indicating that there may be uncharacterized inflammatory pathways in KLICK syndrome, similar to some other ichthyoses. The aim of this work was to characterize KLICK syndrome at the cellular and molecular level. A lesional skin biopsy was obtained, following informed consent, from a 32-year-old woman with KLICK syndrome. Sanger sequencing confirmed the presence of the homozygous single nucleotide deletion in the 5′ untranslated region in POMP. Skin architecture was assessed using immunostaining, which revealed dynamic proliferative keratinocytes, precocious expression of involucrin and loricrin, and retention of loricrin in the stratum corneum. Lymphocytic infiltrates in the upper dermis were suggestive of inflammation and imaging mass cytometry was used to visualize and identify the immune subsets present. RNA sequencing revealed dysregulated pathways relating to keratinocyte differentiation, keratinization, cornification, and interferon signalling. Functional classification of differentially expressed genes using PANTHER additionally implicated WNT signalling, EGFR signalling and inflammatory signalling pathways as dysregulated in KLICK syndrome. KLICK syndrome can therefore be characterized as a hyperproliferative inflammatory skin disorder. Using a reverse transcriptomics approach, epidermal growth factor receptor (EGFR) inhibition and phosphoinositide 3-kinase (PI3K) inhibition were identified as potential treatment options that warrant further investigation. Understanding the pathobiology of KLICK syndrome may yield novel mechanisms driving inflammatory skin disease, which may be therapeutically targetable in patients with currently limited treatment options. [ABSTRACT FROM AUTHOR]