title: Genetic analysis of inherited canine neurological disorders
Creators: name: Christen, Matthias Theo
Publisher: name: Universität Bern
Year: 2023
Subjects: subject: 570 Life sciences; biology
subject: 590 Animals (Zoology)
subject: 610 Medicine &amp; health

description: Comparable to human medicine, neurological disorders in dogs represent a category of diseases with often progressive and severe phenotypes. These conditions can drastically impair normal life and lead to lasting disabilities, movement disorders, or even premature death. In recent years, the availability of medical care for companion animals has reached levels that are comparable with the standards in human medicine. However, many neurological diseases remain untreatable for humans and their canine companions alike. Simultaneously, the unique population structure of modern dog breeds with very little genetic variation within specific breeds facilitates the fast spreading of spontaneous genetic variants that can lead to the development of diseases, such as inherited neurological disorders. On one hand, this makes dogs valuable models for studying such spontaneously emerging genetic diseases, but on the other hand breeders need methods like genetic tests to stop new variants from spreading.
In this thesis, I analyzed the genetic background of seven diverse inherited canine neurological phenotypes. My research involved different genetic mapping methods, whole genome sequencing analysis, and genotyping of selected subpopulations with Sanger Sequencing. Incidentally, all seven investigated phenotypes turned out to be inherited in a fully penetrant, autosomal recessive mode.
A deletion of the complete SELENOP gene in Belgian Shepherd dogs led to a selenium deficiency which was in turn associated with juvenile onset cerebellar ataxia. Another ataxia phenotype was investigated in Nova Scotia Duck Tolling Retrievers and associated with a missense variant in SLC25A12. A third type of hereditary ataxia, more precisely an exercise induced dystonia-ataxia syndrome, was studied in Weimaraner dogs. I was able to connect this phenotype with a candidate causative frameshift variant in TNR, coding for the extracellular matrix protein tenascin, which is specific to the central nervous system.
Another type of neurological disease that was studied as part of this work was a hereditary sensory and autonomic neuropathy (HSAN) in mixed breed dogs, which was associated with a variant in SCN9A, a known human candidate gene for HSAN and congenital insensitivity to pain. The large and heterogeneous group of inherited errors of metabolism yielded candidate causative variants for three different phenotypes. ACADM and MFF were both associated with phenotypes affecting the metabolism and homeostasis of mitochondria in neurons and throughout the body. The variants were specific to Cavalier King Charles Spaniels with medium-chain acyl CoA deficiency and Bullmastiffs with mitochondrial fission encephalopathy, respectively. Lastly, a MYO5A frameshift variant showed the expected co-segregation for a monogenic autosomal recessive defect in a litter of miniature Dachshunds with a single puppy suffering from coat color dilution and neurological defects.
The identification of these seven candidate causative variants enabled genetic testing and controlled breeding. The long-term goal of eradicating the corresponding disorders from the target breeds and thus increasing breed- and overall animal welfare will become achievable with the availability of such tests. Most of the variants we identified were in known candidate genes for human disorders.
However, SELENOP variants have never been reported as the cause for human neurological disorders. This thesis, therefore, demonstrates that genetic analysis of inherited canine diseases continues to offer the chance of gaining new biological insights that might be valuable for human medicine in the future.