CF-like disease in dogs linked to altered CFTR function: Study
Findings may help in developing animal models, identifying treatment targets
A disease found in dogs where abnormally thick mucus accumulates in the gallbladder — called a mucocele — is characterized by altered levels and function of the CFTR protein that’s also faulty in cystic fibrosis (CF) patients, according to recent research.
In contrast to the disease in humans, which is similarly characterized by abnormal mucus buildup, no underlying mutations in the CFTR gene were identified by researchers that could explain the faulty protein in the canine condition.
The findings open doors for better understanding of factors that contribute to CF-like diseases, developing new animal models, and identifying treatment targets.
Identifying underlying cause of CFTR dysfunction in dogs
“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,” Jody Gookin, PhD, a professor at North Carolina State University and the study’s corresponding author, said in a university news story.
The study, “Acquired dysfunction of CFTR underlies cystic fibrosis-like disease of the canine gallbladder,” was published in the American Journal of Physiology – Gastrointestinal and Liver Physiology.
In CF, mutations in the CFTR gene lead to a deficient or faulty CFTR protein that’s normally important for regulating the flow of salt in and out of cells. Essentially, CFTR acts as a gated channel through which water and chloride ions, a type of salt particle, move.
A normal balance enables production of a mostly water-based mucus that’s easily moveable and protects and lubricates tissues. However, with CF-causing mutations, these channels don’t work right or there aren’t enough of them on the cell surface, so mucus is thicker and stickier than usual. It then accumulates in tissues throughout the body, disrupting normal organ function.
CF is not known to naturally develop in dogs, but the animals can develop a disease with some notable similarities called mucocele of the gallbladder, where cysts of thick and sticky mucus obstruct the normal function of the gallbladder, a small organ near the liver that’s involved in digestive functions. This condition is seen mostly in purebred dogs.
Gallbladder disease first observed in handful of dog breeds about 20 years ago
“We really only started seeing this disease about 20 years ago in a handful of breeds,” Gookin said. “What captured my attention was how similar these gallbladders looked to those in animal models of CF.”
The scientist went on to explain that animal models of CF, in which the CFTR gene is genetically silenced, develop gallbladder disease that looks like the naturally occurring canine condition.
“That led us to wonder whether dogs with mucoceles had a mutation in CFTR,” Gookin said.
To learn more, the scientists performed genetic sequencing of CFTR using blood samples from 2,642 dogs, including eight Shetland sheepdogs with established mucocele formation, 115 dogs considered based on their breed to be “high risk” for mucoceles, and 2,519 dogs considered to be “low risk.”
The analysis did not show any differences between the three groups in terms of the types of CFTR mutations. For dogs with mucoceles, no mutations were found in parts of the gene where CF-causing mutations are found in humans.
When examining gallbladder tissue from affected and non-affected dogs, the researchers did find, however, that the actual function of the CFTR protein was altered in dogs with mucoceles and its levels were lower than normal. Specifically, CFTR-dependent secretion of negatively charged particles was reduced.
Gene activity of CFTR, as well as related genes involved in ion transport, were reduced in the diseased gallbladders.
Canine disease with ‘uncanny similarity’ to CF
Overall, the study demonstrates the presence of a canine disease with “uncanny similarity” to CF that’s “driven by underlying failure of CFTR function,” the researchers wrote.
The possibility of a CF-like disease emerging without an underlying genetic mutation in the CFTR gene is “the most eye-opening piece,” Gookin said.
“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,” she added.
The scientist indicated that other genes or environmental factors might be influencing CFTR function in the dogs.
“Our next steps will be looking at the entire genome of these dogs to see if there are other mutations that could be a factor — if there’s something else in their genome that makes them susceptible to developing this disease,” Gookin said.
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