Genetic analysis of genodermatoses

The skin is the largest organ of the body. It provides a barrier that protects the body from harmful environmental factors as well as from a loss of fluids. Impaired skin integrity can lead to a disruption of the skin barrier and to disease. Genodermatoses are a heterogenous group of mostly rare single gene disorders affecting the skin and its appendages. After decades of genetic and due to recent advances in technology, the genetic cause of numerous genodermatoses was uncovered. Based on the function of the involved genes and the affected skin compartments, monogenic skin disorders can be grouped into ichthyoses, epidermolysis and blistering disorders, pigmentation disorders, disorders of ectodermal appendages, vascular disorders, connective tissue defects, dermal mosaics, and genodermatoses with tumor predisposition. Many human genodermatoses have a very similar counterpart in animals. Spontaneous mutants in purebred animals such as dogs that have a unique population structure and physical similarity to humans, are therefore valuable models for human genodermatoses. In this thesis, I took part in the analysis of 12 canine, equine and feline phenotypes with manifestations in skin or its appendages applying different genetic mapping techniques and whole genome sequencing. In cats, a frameshift variant in the COL5A1 gene was identified in a single case with Ehlers-Danlos syndrome. In a female cat with inflammatory linear epidermal lesions, a missense variant in the X-chromosomal NSDHL gene was found, explaining the observed cutaneous mosaicism. Interestingly, I identified a large deletion in the same gene, NSDHL, underlying a related congenital cornification disorder in a Labrador Retriever and her equally affected crossbred daughter. In a single canine case of ichthyosis, whole genome sequencing revealed a de novo variant in the ASPRV1 gene, probably disturbing filaggrin processing during cornification. A deregulation in cornification of nasal keratinocytes was also suspected in a litter of Greyhounds with nasal parakeratosis, in which I identified a splice defect in the SUV39H2 gene. Pigmentation and hair texture are diverse in dogs. During a study in Chow Chows with coat colour dilution I identified a variant in the MLPH gene encoding melanophilin, and found that this variant segregated in other dog breeds as well. In dogs with oculocutaneous albinism, variants in OCA2 and SLC45A2 encoding transporters in membranes of melanosomes were identified. In dogs with a previously unknown cause for their curly coat, a candidate gene approach led to the identification of a second KRT71 allele for curls, which has a potential predisposing role for hair loss that warrants further investigation. Hairless skin patches on the head and back was also a prominent feature in male Dachshund puppies with X-linked hypohidrotic ectodermal dysplasia, where a single base deletion in the EDA gene was found using targeted Sanger sequencing. Lethal acrodermatitis in Bull terriers is a disorder causing early death of affected animals. All cases in our cohort were homozygous for a splice defect in MKLN1, a gene not yet described in human genodermatoses. Finally, in horses from the Akhal-Teke breed, I identified a nonsense variant in the ST14 gene most likely causing the lethal naked foal syndrome in a monogenic autosomal recessive mode. The identification of these candidate causative variants enables genetic testing, controlled breeding and in the long term eradication of the corresponding disorders from the animal population. The majority of identified variants was located in genes already known from human disorders. However, ASPRV1 and MKLN1 variants have never been reported as cause for human genodermatoses. This thesis therefore demonstrates that genetic anlysis of spontaneous animal mutants offers the chance to gain new biological knowledge and candidate genes for rare human genodermatoses