A Genetic Basis for Addison’s Disease in Nova Scotia Duck Tolling Retrievers

Addison’s disease (hypoadrenocorticism) has been reported in many dog breeds, but it is especially common in Nova Scotia Duck Tolling Retrievers (NSDTRs). Not only are NSDTRs more prone to Addison’s disease, but they also tend to be affected at an earlier age.

Researchers have now identified a specific genetic variant associated with juvenile-onset Addison’s disease in NSDTRs, according to a paper published in Scientific Reports.

Previous research on Addison’s disease in NSDTRs

Scarlett Varney, DVM, a PhD candidate at UC Davis School of Veterinary Medicine and a lead co-author of the study, explained that this research was motivated by previous observations related to Addison’s disease in NSDTRs.

The average age of Addison’s diagnosis in dogs is 4 years old. Two earlier findings suggested NSDTRs were an exception. A 2007 study found NSDTRs develop Addison’s disease earlier, at an average age of just 2.6 years old. Additionally, a 1997 report identified 5 young, closely related NSDTRs with juvenile-onset Addison’s disease, some of which showed signs of additional autoimmune conditions. “Having multiple cases of juvenile-onset Addison’s disease within a single breed, particularly within a litter, was a strong signal of an underlying genetic cause,” Varney said.

A link between Addison’s disease and other autoimmune conditions

Breeders of NSDTRs contributed genetic samples and medical histories from 60 dogs with Addison’s disease for this study. This included 24 dogs with juvenile-onset Addison’s disease, diagnosed prior to 1 year of age.

Nineteen of the 24 dogs with juvenile-onset Addison’s disease (79%) had additional autoimmune diseases. Comorbidities included immune-mediated cytopenias, inflammatory bowel disease, and conjunctivitis. Dogs with juvenile-onset Addison’s disease were also at an increased risk of early death due to concurrent autoimmune diseases.

“We were surprised by how many dogs in the cohort had concurrent and often severe autoimmune conditions,” Varney said. “This ultimately led us to recognize that juvenile-onset Addison’s disease in these dogs may represent a manifestation of a broader multiple autoimmune syndrome rather than isolated adrenal disease.”

Genetic basis for juvenile-onset Addison’s disease

Genetic analysis identified a specific mutation in the RESF1 gene associated with juvenile-onset Addison’s disease. Of the 24 dogs with juvenile-onset Addison’s disease, 22 were homozygous for the RESF1 variant and 1 was heterozygous. None of the cases diagnosed after 1 year of age were homozygous for the RESF1 variant, though 6 were heterozygous. Further analysis of a larger sample of dogs determined that the RESF1 variant had 76% penetrance, meaning it was associated with juvenile-onset Addison’s disease in 76% of homozygous dogs.

This particular RESF1 variant is specific to NSDTRs, but Varney said variants elsewhere in the RESF1 gene are plausible in other breeds and worth investigating. The region of RESF1 containing the variant is highly conserved across mammal species, including humans. Therefore, the findings of this study may inform future research in both human and veterinary medicine.

The public’s role in veterinary research

This study highlights the valuable role that dog owners and breeders can play in genetic research. The genetic samples and medical histories used in this study were all voluntarily submitted by NSDTR breeders and owners.

“This research was a collaborative effort,” said Varney. “Affected dog owners and NSDTR breeders were essential to the study,” she added. This study reflects a broader pattern in breed-specific research, which often depends on contributions from breeders and pet owners to gather sufficient samples and case histories.

Clinical implications for veterinarians

“The most important takeaway is that a young NSDTR presenting with Addison’s-like symptoms should be tested for Addison’s disease,” Varney said. If Addison’s is confirmed, the patients should also be tested for the RESF1 variant through the UC Davis Veterinary Genetics Laboratory.

Additionally, the diagnosis of Addison’s disease in a young NSDTR should prompt evaluation for other autoimmune conditions. Client education and careful patient monitoring are recommended in these cases, to allow for early diagnosis and treatment of other autoimmune diseases.

Finally, Varney recommended testing for the RESF1 variant before breeding any NSDTR, noting encouraging early results: “Since implementation of genetic testing, no additional juvenile-onset Addison’s disease dogs from tested parents have been reported to our knowledge.”

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