Identification and characterization of genes for skin and hair disorders

Abstract

The skin, as the outermost organ of the human body along with its appendages (e.g. hair), possesses a remarkable capacity for self-regeneration, as well as social and functional significance, distinguishing it from many other tissues. Skin and hair disorders comprise conditions in which affected individuals display one or more of the following features: dyspigmentation (e.g. Cole disease, COLED); abnormal skin structure (e.g. epidermodysplasia verruciformis, EV); or abnormal hair structure and growth (e.g. monilethrix). Skin and hair disorders develop as a consequence of genetic and/or environmental factors. In some cases, genetic influence manifests as a direct causative factor, as exemplified by monogenic disorders such as monilethrix or COLED. While significant progress has been made in identifying causal genes for several skin and hair disorders, others remain unexplained. Further research is required to elucidate the underlying molecular genetic mechanisms, which can improve diagnostic accuracy and facilitate the development of therapeutic strategies. <br/> Therefore, the aim of the present thesis was to genetically elucidate rare monogenic skin and hair disorders by identifying novel pathogenic variants and/or genes, and their underlying pathomechanisms. <br/> In all three studies included in the present thesis, we performed Sanger and/or exome sequencing (ES) in DNA from patients affected by skin and hair disorders, namely, COLED, EV, and monilethrix. We identified novel pathogenic variants in genes previously associated with COLED and EV and, for the first time unraveled a novel type I keratin gene as the genetic basis of monilethrix, that is <em>KRT31</em>. In detail, we identified a novel pathogenic variant in <em>ENPP1</em> in the somatomedin-B-like 2 (SMB2) domain in a family with COLED. In a consanguineous family with four individuals affected by EV, we identified a novel pathogenic variant in <em>TMC8</em> leading to abnormal splicing. And we found a nonsense variant in <em>KRT31</em> as a novel cause of monilethrix in six individuals from four unrelated families. We performed cell culture experiments, e.g. immunoblotting, immunofluorescence and reverse transcription quantitative real-time polymerase chain reaction (RTqPCR), to confirm the pathogenicity of the variant. <br/> With these results, we have expanded knowledge on genetic hair and skin disorders. In particular, we have: i) broadened the genetic spectrum of <em>ENPP1</em>-associated COLED; ii) expanded the mutation spectrum of EV by identification of a <em>TMC8</em> variant; and iii) first unravelled a pathogenic variant in <em>KRT31</em> as cause of autosomal dominant monilethrix.