Polymyositis in the Dutch Kooikerdog

Introduction: In the Dutch Kooiker dog, an inflammatory myopathy exists that presents itself with clinical signs of dysphagia, locomotion problems, or a combination of both. The outcome of this disease is fatal since most affected dogs died within 2 years after diagnosis.
Method: We identified over 170 affected Kooiker dogs, originating from various countries, of which the clinical signs, histopathology, immunohistochemistry were inventoried. To unravel the possible genetics behind this disease a genome wide association study (GWAS), next generation DNA sequencing (NGS) and an expression study was performed.
Results: Histopathological revealed an inflammatory, primarily lymphohistiocytic polymyositis. Immunohistochemistry showed that CD3+ T-cells were the predominant inflammatory cell type, accompanied by CD8+ cytotoxic T-cells, MHC-I class positive staining on muscle sarcolemma, MHC-II class molecules expression on myofibers. A GWAS of 33 cases and 106 controls that indicated the involvement of a region on chromosome 19 containing the cytokine gene pair IL21 and IL2 (praw = 2.1*10-14). A NGS revealed that 8 cases shared a 39 kb deletion, situated 10 kb upstream of IL21. Leukocytes of affected, untreated dogs that were homozygous for the deletion overexpress IL21 and IL2 after stimulation with mitogens
Discussion: These findings suggest that elements located 10 – 49 kb upstream of the IL21/IL2 gene pair play an important role in the regulation of the canine genes and that deletion of these elements is a risk factor for polymyositis in Kooiker dogs and can be used to eradicate this disease.