Genetic investigation of inherited skin diseases in cats and dogs

The skin is the largest organ in the body and performs many vital functions. Its structure and integrity can be compromised by various external and internal factors. One such disruption can result from the consequences of deleterious genetic variants, leading to skin disease. In humans, over 1,500 monogenic diseases with skin involvement have been described. In veterinary medicine, skin problems are one of the most common reasons for a visit in a veterinary practice and genetic factors are included in the wide range of causes of skin diseases. The number of known heritable skin diseases in cats and dogs is significantly lower compared to humans, however, it is rapidly increasing.
Within my PhD thesis I investigated 16 inherited skin diseases in cats and dogs with the aim of identifying the underlying genetic defects. According to their clinical manifestation, these can be grouped into distinct disease categories. My research includes skin diseases classified as cornification disorders, blistering disorders, connective tissue disorders, and skin appendage disorders. In the group of cornification disorders, there were four new breed-specific types of ichthyoses caused by variants in ABHD5 (Golden Retriever), KRT1 (Shar Pei), KRT10 (Chihuahua), and SDR9C7 (Chihuahua). Moreover, footpad hyperkeratosis in a Rottweiler caused by a variant in DSG1, and Darier disease in a Shih Tzu caused by a variant in ATP2A2 were included among the studied cornification disorders. Several forms of epidermolysis bullosa were investigated belonging to the group of blistering disorders: epidermolysis bullosa simplex in a Welsh Corgi (Cardigan) caused by a variant in KRT5, dystrophic epidermolysis bullosa in neonatal Basset Hounds caused by a variant in COL7A1, and junctional epidermolysis bullosa in two unrelated domestic shorthair cats and in a litter of Australian Shepherds caused by variants in COL17A1 and LAMB3, respectively. I investigated various forms of Ehlers-Danlos syndrome within the group of connective tissue disorders. In a family of domestic shorthair cats, dermatosparaxis Ehlers-Danlos syndrome was caused by a variant in ADAMTS2. Classical Ehlers-Danlos syndrome in a Chihuahua was caused by a variant in COL5A2. The same form of the syndrome was diagnosed in a Bengal, a domestic shorthair cat, and two sibling Bombays, all resulting from three independent variants in COL5A1. Two of the studied skin disorders affected skin appendages, namely hair shaft dysplasia in two unrelated domestic shorthair cats caused by individual variants in DSG4, and sebaceous gland dysplasia in two domestic shorthair kittens caused by a variant in SOAT1. And lastly, I investigated acrodermatitis enteropathica, a miscellaneous disorder in a litter of Turkish Vans. The zinc deficiency disorder manifested with severe signs of skin disease and was caused by a variant in SLC39A4.
The results from this PhD thesis highlight the potential of next-generation sequencing technologies to identify underlying pathogenic variants in inherited skin diseases in cats and dogs. Knowledge about the disease-causing gene and understanding of the underlying pathomechanisms often resulted in a definitive diagnosis for the patient, which in turn could lead to a more accurate prognosis, thoughtful breeding recommendations, better management of the disease, and guidance for targeted therapy. Such a precision medicine approach in veterinary medicine is not only beneficial for the animals but also enhances knowledge of rare skin diseases that can be transferred to human medicine, demonstrating the value of a One Health approach.

2023

dissertation

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