Identification of Novel Mutations and Molecular Pathways for Canine Neurodegeneration and Chondrodysplasia
Year: 2015
Type: dissertation
Abstract: Inherited diseases occur across different species. This thesis work has provided insights into the molecular genetic background of three autosomal recessive diseases that affect specific dog breeds. The studied phenotypes comprised two neurodegenerative diseases and a type of skeletal dysplasia. Genome-wide methods, such as SNP chip genotyping, were used to identify disease-associated gene variants. In all three disease phenotypes, the likely causative variant was found in a gene that had not been previously associated with a monogenic disorder. The Norwegian Elkhound and Karelian Bear Dog breeds are affected with inherited chondrodysplasia that causes short-stature dwarfism of varying severity. A genome-wide association study in Norwegian Elkhounds revealed a disease-associated locus on canine chromosome 17 and a nonsense mutation in the ITGA10 gene. The identified mutation was homozygous in all affected dogs from both breeds, and may have been introduced to Karelian Bear Dogs from Norwegian Elkhounds. The ITGA10 gene encodes an α10-integrin protein that assembles into a collagen-binding α10β1 integrin. The α10β1 integrin is a cell surface receptor, found in growth plate chondrocytes, where it mediates the cell s attachments with the surrounding matrix. Due to the mutation, a full-length α10-protein is not produced, disturbing the growth of long bones. Early-onset cerebellar degeneration occurs in the Finnish Hound dog breed. Neurological examination of affected dogs revealed quickly progressing cerebellar ataxia and failure to thrive. Genome-wide association analyses mapped the disease to a 1.5-Mb locus on canine chromosome 8. Sequencing of the SEL1L gene from the locus identified a homozygous missense mutation in all affected dogs. The mutation causes a serine to proline amino acid change within a highly conserved functional domain of the encoded SEL1L protein. The SEL1L protein is found in the endoplasmic reticulum, where it functions within a protein quality control and degradation pathway. Cerebellar tissue samples from affected dogs showed signs of endoplasmic reticulum stress, which may be the cause of premature cell death. A novel neurological disease, characterized by juvenile to adult onset cerebellar ataxia, was recognized in the Lagotto Romagnolo breed. Through linkage analysis, homozygosity mapping and whole-genome sequencing, the disease was associated with a homozygous missense change in the autophagy-related ATG4D gene. Pathological examination of affected dogs revealed progressive cerebellar degeneration, and intracellular vacuolar changes both in neuronal and extraneuronal tissues. The ATG4D gene encodes a cysteine protease, which is thought to function in the macroautophagy pathway. The autophagy process degrades and recycles damaged or obsolete cellular materials via membrane-enclosed autophagosomes. In line with this, the neuronal tissues of affected dogs showed signs of altered autophagic flow. Overall, this study has revealed three new disease-linked genes in dogs, which may be associated to similar disorders in other species. On the basis of the results, DNA-tests have been developed for veterinary diagnostic and breeding purposes. Importantly, by shedding light into disease-causing pathways, the results of this study could prove beneficial not just for canine health but for human medicine as well.
Source: Työväentutkimus Vuosikirja
Author: Kyöstilä, Kaisa
Language: English
Subfield: Animal Science and Zoology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2256046243