Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)

Legacy Department


Committee Member

Dr. Leigh Anne Clarke

Committee Member

Dr. Amy Lawton-Rauh

Committee Member

Dr. Meredith Morris

Committee Member

Dr. Christopher Saski


The domestic dog, Canis familiaris, has a unique population structure that lends itself to the study of hereditary diseases. Purebred dogs populations are genetically isolated and as a result are affected by more than 400 naturally occurring diseases, many of which have human counterparts. In the last 15 years, dogs have emerged as a model for the study of human hereditary diseases, fueling the development of resources including a 7.6X coverage reference genome and single nucleotide polymorphism (SNP) genotyping arrays.

Congenital myasthenic syndrome (CMS) is a neuromuscular disorder of both humans and dogs in which transmission across the neuromuscular junction is compromised. Affected individuals exhibit generalized muscle weakness that is exacerbated with exercise. To date, 18 genes are known to harbor mutations causative for CMS in humans. We characterized a novel CMS in a family of Labrador Retrievers. Using whole genome SNP profiles we identified COLQ as a candidate gene. In the neuromuscular junction, ColQ acts as an anchor for acetylcholinesterase, which is responsible for terminating the signal for muscle contraction. Sequencing revealed a missense mutation in exon 14 that predicts the substitution of a threonine for an isoleucine at a conserved position.

The Jack Russell Terrier (JRT) is the first dog breed in which CMS was reported in the 1970s. Immunohistochemistry revealed an acetylcholine receptor (AChR) deficiency in affected dogs. Analysis of microsatellites flanking the five AChR subunit genes indicated that haplotypes encompassing CHRNB1 and CHRNE are consistent with inheritance identical by descent. Sequencing revealed a frameshift mutation in exon 7 of CHRNE (G193RfsX272) that is homozygous in recent CMS cases, as well as those from the 1970s.

Congenital idiopathic megaesophagus (ME) is another neuromuscular condition observed in both humans and dogs characterized by an enlarged esophagus. Affected dogs are unable to move food into their stomachs, resulting in regurgitation and frequent aspiration pneumonia. ME is prevalent among German Shepherd Dogs (GSDs). We employed a genome-wide association study to identify genomic regions harboring genes underlying ME. Using 19 affected and 177 unaffected GSDs, we identified an associated region on chromosome 12.