Genetic mutation linked to fatal autoimmune disease in dog breed

<p>Addison’s disease (AD) results in glucocorticoid and mineralocorticoid deficiencies and is often immune-mediated. While AD is uncommon in dogs, Nova Scotia Duck Tolling Retrievers (NSDTRs) exhibit increased incidence, suggesting genetic predisposition. Detailed clinical evaluation of 24 juvenile-onset cases revealed that while all dogs presented with adrenal insufficiency, at least 10 dogs (41.7%) had concurrent autoimmune conditions. This suggests juvenile-onset AD in NSDTRs represents part of a broader multiple autoimmune syndrome (MAS) with variable expressivity. Strikingly, NSDTRs affected by juvenile-onset AD had severely decreased lifespans, with a median survival of 2 years despite appropriate treatment. Genome-wide association identified a significant association on chromosome 27 (chr27:29,724,286, <em>p</em> = 6.96 × 10^− 13). Whole-genome, short-read sequencing identified a recessive missense variant in <em>RESF1</em> (Chr27:29,736,795). The variant exhibited 76% penetrance for early-onset disease, and the decreased penetrance was not attributable to differences in Dog Leukocyte Antigen (DLA) haplotypes. Immunohistochemistry confirmed T cell infiltration in the adrenal cortex of two unrelated affected dogs, with necropsy findings including severe bilateral lymphocytic adrenalitis, multisystemic granulomatous inflammation, and lymphoplasmacytic conjunctivitis supporting autoimmune pathogenesis. This study identifies <em>RESF1</em> as a novel gene associated with autoimmune disease in NSDTRs, ranging from isolated juvenile-onset AD to multi-organ autoimmune manifestations. The findings represent a rare example of monogenic autoimmune disease and establish <em>RESF1</em> as a candidate gene for further investigation of immune tolerance mechanisms.</p>