Researchers discover cause behind cystic fibrosis-like disease in dogs

Photo: CALLALLOO CANDCY/Adobe Stock

Mucocele formation in dogs, a disease of the gallbladder characterized by the buildup of abnormal mucus, holds similarities to cystic fibrosis (CF) disease in humans.¹ Recent research revealed that this canine gallbladder disease, also known as canine gallbladder mucocele (GBM),² is caused by a dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This differs from the cause of CF in humans, where a mutation in CFTR leads to the disease.¹ The study, which received grants from the Morris Animal Foundation and the National Institutes of Health, may hold significance for human patients with CF and animal models of the disease.¹

Gallbladder mucocele formation is a condition where thick, dehydrated mucus gradually accumulates, disrupting normal gallbladder function and eventually leading to obstruction and rupture. The disease primarily affects purebred dogs, with Shetland sheepdogs being the most commonly affected breed in the United States. In the United Kingdom, border terriers are more commonly affected.¹ Other breeds commonly affected include Miniature Schnauzers and Cocker Spaniels.²

“We really only started seeing this disease about 20 years ago in a handful of breeds,” Jody Gookin, professor of small animal internal medicine at North Carolina State University and corresponding author of the research, said in a news release.¹ “What captured my attention was how similar these gallbladders looked to those in animal models of CF.”

In humans, the thick, immobile mucus seen in CF results from a defect, or mutation, in the CFTR gene. This gene normally deposits channels in epithelial cells that then secrete chloride and water. These channels help keep the mucus moist and mobile by lubricating the cell surface. In CF, the mucus becomes dehydrated and clogs the lungs and intestines due to an absence of these lubricating channels. However, the there is no buildup of mucus in the gallbladder of humans with CF.

Researchers conducted whole genome sequencing on blood samples from 8 Shetland sheepdogs with gallbladder mucocele formation and compared the location and frequency of CFTR gene variants with those found in 115 dogs from 12 breeds at high risk for mucocele formation and 2,519 dogs from 340 low-risk breeds. The comparison revealed no significant differences between the groups. Furthermore, the dogs with mucocele formation did not have CFTR mutations in the regions where humans with CF do.^1,3

“There are no recorded instances of naturally occurring CF in any non-human species, but when researchers study CF in animal models by knocking out the CFTR gene, those animals often develop the same gallbladder pathology that we see in dogs with mucocele formation, said Gookin in the release.¹ “That led us to wonder whether dogs with mucoceles had a mutation in CFTR, but they didn’t. What they did have was a failure of CFTR to function.”

“What that means is that somehow these dogs are acquiring a dysfunction of the CFTR channel that is not based on a defect in the gene,” Gookin continued. “It could be due to the influence of other genes and environmental factors that influence CFTR function.”

Gookin revealed that the most surprising piece from the study for her was that a disease resembling CF could develop without being caused by a mutation in the CFTR gene. “Identifying the underlying cause of CFTR dysfunction in dogs with mucocele formation has important implications for people where similar factors might contribute to CF-like diseases, or reveal new treatment targets for CF,” she said in the release.¹

Going forward, Gookin explained that the research team’s next steps involve examining the entire genome of those dogs to see if there is anything else in their genome that plays a role in the formation of gallbladder mucocele.

References

1. Peake Tracey. How an emerging disease in dogs is shedding light on cystic fibrosis. News release. July 29, 2024. Accessed August 7, 2024. https://news.ncsu.edu/2024/07/how-an-emerging-disease-in-dogs-is-shedding-light-on-cystic-fibrosis/
2. Center SA. Canine gallbladder mucocele. Merck Veterinary Manual. August 2023. Accessed August 7, 2024. https://www.merckvetmanual.com/digestive-system/hepatic-diseases-of-small-animals/canine-gallbladder-mucocele
3. Gookin JL, Holmes JL, Clarke LL, et al. Acquired dysfunction of CFTR underlies cystic fibrosis-like disease of the canine gallbladder. American Journal of Physiology-Gastrointestinal and Liver Physiology. Published online July 23, 2024. https://doi.org/10.1152/ajpgi.00145.2024