2021-11-032024-07-01https://boris-portal.unibe.ch/handle/20.500.12422/31139The skin is the largest organ of the body and its integrity is crucial for survival. In humans and domestic animals, a large number of genetic defects, many of them monogenic, have been identified which affect the skin and/or its appendages (hair follicles, nails, teeth). However, there are still many patients with inherited skin diseases or genodermatoses, in which the causal genes remain unknown, precluding an accurate diagnosis and impeding proper management and precision medicine.The dog and other domestic animals have gained attention during the last ~15 years as attractive model organisms in forward genetics studies. Purebred domestic animals are typically kept as strictly isolated populations with a limited amount of inbreeding, favoring the expression of recessive alleles. This population structure is ideally suited for the identification of the underlying causative genetic variants by hypothesis-free positional cloning approaches. Due to their physiological similarity with humans, a comparative “One Health” approach involving the genetic analysis of spontaneous domestic animal mutants with genodermatoses offers excellent opportunities to unravel unknown genetic variants and genes with direct relevance for the skin.In previous own work on domestic animals with spontaneously arisen genodermatoses, we were the first to identify pathogenic variants in ASPRV1 (ichthyosis), FAM83G (palmoplantar hyperkeratosis and wooly hair), FOXI3 (ectodermal dysplasia), MKLN1 (lethal acrodermatitis), SUV39H2 (nasal parakeratosis) and UNC93B1 (exfoliative cutaneous lupus erythematosus).During the 48 month period of the new proposal, we plan to identify further causative genetic defects for several inherited diseases affecting the skin and/or hair coat in domestic animals:•Nasal hyperkeratosis in Bengal and Egyptian Mau cats (NH)•Ichthyosis 2 in Golden Retrievers (ICH2)•Alopecia X in Pomeranians (AX)NH and ICH2 are relatively young genodermatoses and together with our collaboration partners, we plan to compile the first comprehensive characterization of their clinical and histopathological phenotypes. Using a highly developed set of genetic methods, we will try to identify the causative genetic variants for all three genodermatoses and further new phenotypes that will become available during the project. If the causative genetic variants turn out to be located in genes with well characterized functions, our work will be complete. However, while this initial part of the plan research is admittedly hypothesis-free and of exploratory nature, it offers the chance to also identify causative variants in previously uncharacterized genes and to thus generate truly novel, exciting and testable hypotheses. If our research identifies “new genes” for a given phenotype or if it extends a previously established genotype-phenotype correlation, we will further characterize the function of the altered genes and investigate the molecular pathogenesis of the studied phenotypes.The identification of causative genetic defects will provide new candidate genes for human and veterinary genetics. The research will identify functional pathways improving our understanding of potentially devastating inherited diseases, as well as the appraisal of new genotype-phenotype correlations. This work will be relevant for basic science but has also important implications for application in veterinary diagnostics and animal welfare. Our research will enable the introduction of genetic testing and targeted breeding programs to combat inherited diseases in domestic animals.enDewey Decimal Classification::500 - Science::570 - Life sciences; biologyDewey Decimal Classification::600 - Technology::630 - AgricultureDewey Decimal Classification::500 - Science::590 - Animals (Zoology)Dewey Decimal Classification::600 - Technology::610 - Medicine & healthRNA-seqdermatologywhole genome sequencingkeratinocyteGWASanimal modelalopeciahair folliclerare diseaseskincatgenodermatosisdoggeneticslinkagehorsefibroblast