UC Davis links RESF1 variant to juvenile Addison’s in Tollers: full analysis
UC Davis scientists say they’ve found the gene variant behind a juvenile form of Addison’s disease in Nova Scotia Duck Tolling Retrievers, a breed with a long-recognized predisposition to hypoadrenocorticism. The newly published Scientific Reports study links a recessive missense variant in RESF1 to early-onset disease and multiple autoimmune syndrome in young Tollers, and UC Davis has already launched a breed-specific DNA test through its Veterinary Genetics Laboratory. (nature.com)
The finding builds on years of work suggesting that Addison’s disease in Tollers has a strong inherited component. A 2007 JAVMA report on 25 cases from 1994 to 2006 found the disease appeared to follow an autosomal recessive mode of inheritance in the breed, with very high heritability. Earlier candidate-gene work and dog leukocyte antigen studies also pointed toward immune-mediated disease biology, but they did not identify the causal variant now reported in RESF1. (pubmed.ncbi.nlm.nih.gov)
In the new study, investigators clinically characterized 24 juvenile-onset cases and reported that all had adrenal insufficiency, while at least 41.7% had concurrent autoimmune conditions. The genome-wide association signal mapped to chromosome 27, and sequencing identified a recessive missense variant in RESF1. The authors reported 76% penetrance for early-onset disease, and pathology from two unrelated affected dogs showed T-cell infiltration and bilateral lymphocytic adrenalitis, findings that support an autoimmune mechanism. They also reported a median survival of 2 years despite treatment in affected juvenile-onset dogs, underscoring the severity of this presentation. (nature.com)
UC Davis’ companion announcement framed the discovery as relevant beyond canine breeding. The university noted that RESF1 has not previously been associated with Addison’s disease or multiple autoimmune syndrome in humans, despite the gene being highly conserved across species. That makes Tollers a potential natural model for studying autoimmune endocrine disease, not just a breed-health case study. (ucdavis.edu)
On the implementation side, the Veterinary Genetics Laboratory’s new Juvenile Addison’s Disease, or JADD, test gives breeders and veterinarians something actionable now. The lab says affected puppies average about 5 months of age, though reported cases have ranged from 8 weeks to 12 months, and that dogs with two copies of the variant have about a 75% chance of developing Addison’s disease by 1 year of age. The test is reported as normal, carrier, or affected, reflecting autosomal recessive inheritance with incomplete penetrance. UC Davis also notes that about 20% of Tollers were carriers when the mutation was characterized. (vgl.ucdavis.edu)
Why it matters: For veterinary professionals, this is most useful as both a diagnostic clue and a breeding-management tool. In practice, a young Toller presenting with lethargy, GI signs, failure to thrive, or atypical ophthalmic inflammation may now warrant a lower threshold for considering juvenile Addison’s disease, especially when there’s a family history or concurrent immune-mediated disease. It also sharpens pre-breeding counseling: the test can help avoid producing affected puppies, but because penetrance is incomplete, genotype won’t map perfectly to phenotype, and it shouldn’t replace clinical vigilance. (vgl.ucdavis.edu)
There’s also an important nuance for clinicians and breeders alike: this appears to explain a juvenile inherited form of Addison’s in Tollers, not necessarily every Addison’s presentation in the breed. UC Davis’ Center for Companion Animal Health still lists work underway on adult-onset Addison’s disease in Nova Scotia Duck Tolling Retrievers, suggesting the breed’s overall hypoadrenocorticism burden may involve more than one genetic pathway or phenotype. (ccah.vetmed.ucdavis.edu)
What to watch: The next phase will likely center on uptake of the JADD test in breeding programs, publication of additional phenotype-genotype data, and whether human endocrine researchers begin evaluating RESF1 in unexplained autoimmune Addison’s disease cohorts. (ucdavis.edu)