Genetic characterization of congenital defects in dogs : caudal dysplasia, ectodermal dysplasia and mucopolysaccharidosis VII

• Main Author: Hytönen, Marjo
• Other Authors: Lingaas, Frode, University of Helsinki, Faculty of Veterinary Medicine, Department of Veterinary Biosciences, University of Helsinki, Institute of Biomedicine, Biochemistry and Developmental Biology, University of Helsinki, Research Programs Unit, Molecular Neurology, The Folkhälsan Institute of Genetics, Department of Molecular Genetics, Helsingin yliopisto, eläinlääketieteellinen tiedekunta, Helsingfors universitet, veterinärmedicinska fakulteten, Lohi, Hannes, Sainio, Kirsi
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: Helsingin yliopisto 2013
• Subjects: genetiikka; Canis lupus
• Online Access: http://hdl.handle.net/10138/40222

Since the sequencing of the Canis lupus familiaris genome the dog has become a powerful tool for scientists. Selective breeding has created more than 400 different breeds each representing genetic isolates with breed-specific morphological and behavioral characteristics. Unique population history, available genealogical records, veterinary diagnostics and novel genomic tools greatly facilitate gene mapping studies in dogs. Given that over 600 genetic disorders have been described in dogs and that most of them are similar to human conditions, dogs have emerged as a clinically relevant model for human inherited disorders. This study explores the genetics of three different inherited developmental defects in dogs, caudal dysplasia, ectodermal dysplasia, and mucopolysaccharidosis VII, which all have counterparts in human. In this study, various clinical and pathological techniques have been used to characterize the phenotypes, and genetic methods such as genome-wide association studies and next-generation sequencing to resolve the genetics of the diseases. Moreover, functional studies in mice have been performed to explore the molecular role during embryonic development. The discoveries made here have established the affected breeds as models to further explore disease mechanisms and therapeutic methods, identified new disease pathways, and offered novel approaches for further developmental studies. Furthermore, this work has enabled the development of genetic tests for breeding purposes. Three different phenotypes have been investigated in this study. First, we studied genetics of caudal dysplasia, which in its mildest form is presenting as short-tail phenotype in dogs. A mutation in T (brachyury homolog) was earlier identified to cause this phenotype in Pembroke Welsh Corgis. Homozygous mutations of T in mouse result in severe caudal dysplasia and embryonic lethality suggesting an essential role for the T gene during mammalian development. The presence of the documented T mutation, c.189C>G, was investigated in ...