Browsing by Subject "SOX5"

Progressive retinal atrophy or PRA is a collective term for a group of hereditary degenerative retinal diseases in dogs. PRA affects the photoreceptor cells of the eye ultimately progressing into complete vision loss. Documented in over 100 breeds, it is the most common type of canine retinal diseases. PRA is considered a homologous disease to human retinitis pigmentosa, thus providing a large animal model for studying retinal biology and genetic aetiology of its diseases. The objective of this thesis was to study the genetic cause of a novel form of PRA in young Finnish Lapphunds. Analysis built upon a combination of gene mapping methods and analysis of next­ generation sequencing data. Gene mapping was performed with two analysis methods, genome­-wide association study and homozygosity mapping, utilising single nucleotide polymorphism microarray based genotype data. Identifying a clinical phenotype from the canine biobank at the University of Helsinki resulted in a study cohort of six case and 10 control dogs. Combined with pedigree information, this early­-onset PRA was most likely a new autosomal recessive condition in the breed. Genome­-wide analyses resulted in the discovery of a disease­-associated locus on chromosome 27. Findings of single nucleotide variant filtering of one whole-­genome sequenced affected dog led to the prioritisation of an intronic substitution variant (T > C) in SOX5 gene as a potential cause of PRA. Genetic validation of the variant with 23 dogs showed promising results. Four out of five affected dogs were homozygous for the variant, while controls were either wild-type or heterozygotes. As a result, a previously unknown disease locus was successfully identified, suggesting a possible new spontaneous canine model of retinitis pigmentosa. By better understanding the patho­physiological processes of disease, improved diagnostics and marker­-based testing as well as novel therapies can be developed for both dog and man. However, further studies are needed to understand the underlying molecular mechanism of the candidate disease variant.