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Genetic skin diseases Hans Christian Hennies, Katja Eckl The skin, the largest human organ, is a highly structured, multi-layered organ that is indispensable for the protection of  the organism from the environment. It is particularly exposed, together with lung and gut, and prone to potential life-  threatening reactions of external agents. It exhibits not only a clearly defined morphology but is also characterized by a  close interplay with the immune system, which complements structural features in the defence line against hostile  intruders. The dermatogenetics research group is especially interested in the molecular characterization of rare skin diseases. We  have mainly focused on severe disorders of keratinization, including generalized autosomal recessive congenital  ichthyoses (ARCI) and palmoplantar keratodermas. Using homozygosity mapping and high-throughput sequencing  techniques, we have been analysing the mutation spectrum in ARCI, which can be caused by mutations in more than nine  different genes. Using exome sequencing combined with linkage analysis, we have for the first time identified mutations  in CERS3, the gene for ceramide synthase 3, associated with ARCI and revealed the importance of very long acyl chain  ceramides for epidermal barrier function . A major impediment to translational research in rare skin diseases stems from the lack of suitable disease models. We  have generated in vitro full-skin models for congenital ichthyosis and other keratinization disorders with primary  keratinocytes and fibroblasts using either patient cells or inactivation of single genes through RNA interference.  Availability of patient keratinocytes, however, is often very limited and their ability to proliferate is restricted to few  passages; RNA interference, on the other hand, can also interfere with other, unwanted pathways. We have therefore  embarked on the use of induced pluripotent stem (iPS) cells for skin modelling. To this end, patient fibroblasts are  reprogrammed with stemness factors, and iPS cells are differentiated to the epithelial fate and further to epidermal  keratinocytes. These cells can be used for generating skin models, analysing specific therapeutics, and also systematic  investigations of potential drugs. Current therapy for ARCI is still mostly symptomatic, and topical application of drugs is impeded by the epidermal barrier activity and difficulties in the bioavailability over larger skin areas. We have therefore  tested the efficacy of recombinant enzyme as a drug for topical application in ARCI using transglutaminase 1 deficient  skin models. The protein was transferred to the epidermis with the help of nanotransporters, and the epidermal barrier  function was indeed effectively reconstituted after repeated treatments of the ARCI skin model with enzyme/transporter formulations. Based on these results we are confident that locally substituted proteins are functional in the viable  epidermis and can compensate for the defects of disease-associated genes.
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