Identification of genes involved in genetic diseases in human and dog : from dermatology to neurology

• Main Author: Plassais, Jocelyn
• Other Authors: Rennes 1, André, Catherine
• Format: Thesis
• Language: French
• Published: 2014
• Subjects: Génétique animale; Génétique humaine; Modèle canin; Kératodermie; Neuropathie sensitive; Human genetics; Animal genetics; Dog model; Hyperkeratosis; Neuropathy; anthro-se; phil; Canis lupus
• Online Access: http://www.theses.fr/2014REN1S105/document

The dog species (Canis lupus familiaris) contains more than 350 distinct breeds resulting from human drastic selection during the last centuries. Each breed can then be considered as a genetic isolate, developing specific spontaneous genetic diseases with high frequencies. Thus, dogs constitute a powerful model to identify new genes and alleles involved in disorders homologous to human diseases. For my thesis, I worked on two main topics. The first one focused on the search of the genetic causes of two footpad keratodermas in the Irish terrier and the dogue de Bordeaux breeds. Concerning the Irish terrier, the work was conduced by Tosso Leeb’s team in the University of Berne, in collaboration with the Antagene Company. Using a Genome Wide Association Study (GWAS) and Next Generation Sequencing (NGS), the mutation in a new gene has been identified in footpad hyperkeratosis in this breed. For the dogue de Bordeaux project, we genotyped more than 170 000 SNPs on over 200 dogs. We then performed a genetic linkage study with a subset of 68 dogs, including 14 affected dogs. We identified a significant locus of 20 Mb on the canine chromosome 9 containing one keratin cluster. Comparing clinical, histopathological and immunochemistry data, keratin 16 appeared as an excellent candidate. The sequencing of the gene revealed a complex mutation leading to a non-functional truncated K16 protein. Quantitative RT-PCR analyses showed a strong decrease of the level of KRT16 expression in affected footpads. These results led to propose the dogue de Bordeaux footpad hyperkeratosis as the first spontaneous model of focal non-epidermolytic palmoplantar keratoderma (FNEPPK). In parallel, I studied an acral mutilation syndrome described in several hunting dog breeds. This neuropathy corresponds to human hereditary sensory and autonomic neuropathies (HSANs) and is characterized by an insensitivity to pain only in the limb. With a classical GWAS strategy, using 24 affected and 30 unaffected dogs, we identified a 1.5 Mb locus in dogs, the ...