A disease in dogs, specifically gallbladder mucocele formation, leads to the buildup of unusual mucus similar to that observed in patients suffering from human cystic fibrosis (CF). This condition arises due to incorrect functioning of the gene related to CF found in humans. This discovery might have significant consequences for human patients with CF and for the development of animal models for the condition.
The condition known as gallbladder mucocele results from a gradual build-up of thick, dehydrated mucus that disrupts the normal activities of the gallbladder, ultimately causing blockage and possible rupture. Primarily, this issue affects purebred dogs — in the U.S., Shetland sheepdogs are the most commonly affected breed, while in the U.K., it’s border terriers.
“This disease has only been recognized in the last 20 years in a few dog breeds,” comments Jody Gookin, who is a professor of small animal internal medicine at North Carolina State University and the lead author of the study. “I found it intriguing how much these abnormal gallbladders resembled those in animal models for CF.”
The immobile, thick mucus seen in humans with CF arises from a defect in a gene known as CFTR, which is crucial for establishing channels in epithelial cells that secrete chloride and water. These channels help keep the surface of cells lubricated, ensuring mucus remains moist and manageable. In CF cases, the lack of these channels results in dehydration and blockage of the lungs and intestines. However, in humans, the gallbladder does not become filled with dehydrated mucus.
“There haven’t been any known cases of naturally occurring CF in non-human species,” Gookin states. “Yet, when scientists examine CF in animal models by disabling the CFTR gene, those animals frequently develop gallbladder issues that resemble those found in dogs with mucocele formation. This prompted us to explore whether dogs with mucoceles had a mutation in the CFTR gene, but they did not. Instead, they exhibited a failure in the CFTR channel’s function.”
To further investigate, Gookin conducted whole genome sequencing on blood samples from eight Shetland sheepdogs with gallbladder mucocele and compared the CFTR gene variants’ locations and frequencies to 115 dogs from 12 breeds known to be at higher risk for mucocele formation, as well as 2,519 dogs from 340 breeds considered at lower risk. There were no notable differences discovered between the groups. Moreover, dogs with mucocele did not have mutations in CFTR genes where humans with CF have them.
“This suggests that these dogs somehow develop a malfunction in the CFTR channel that isn’t linked to a genetic defect,” Gookin explains. “It may be influenced by the interaction of other genes or environmental factors affecting CFTR’s function. Our forthcoming steps will involve examining the entire genome of these dogs to identify other mutations that may contribute to their susceptibility to this disease.”
“The most surprising aspect for me is the possibility of developing a CF-like disease without a mutation in the CFTR gene. Understanding the root cause of CFTR dysfunction in dogs with mucocele formation could provide important insights for humans, where similar factors might lead to CF-like conditions — or even highlight new potential treatment avenues for CF.”
This research is published in Gastrointestinal and Liver Physiology and received funding from the Morris Animal Foundation (grant D17CA-068) and the National Institutes of Health (grants T35OD011070 and K01 OD027058). Co-authors from NC State include research technicians Jenny Holmes and Stephen Stauffer; veterinary student Nicole Torres-Machado; former veterinary student Bryanna Meredith; postdoctoral fellow Michael Vandewege; radiologist Gabriela Seiler; small animal surgeon Kyle Matthews; and Kathryn Meurs, Dean of the College of Veterinary Medicine. Contributions to this work were also made by Steven Friedenberg from the University of Minnesota St. Paul and Lane Clark from the University of Missouri, Columbia.
