High mortality among young wetterhoun dogs due to an immunodeficiency
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The Wetterhoun is an old Dutch hunting dogbreed which consists of a very small population. Inbreeding is a big risk within the population and the Wetterhoun association realizes this and therefore takes the necessary measures to prevent inbreeding problems. But despite these measures the Wetterhoun association is since 15 to 20 years dealing with an unexplained high mortality among the Wetterhoun pups. The young dogs die seven to twelve weeks of age after a period of diarrhea followed by neurological symptoms. The first serum immunoglobulin analysis and pathology reports pointed in the direction of a severe kind of immunodeficiency in these young dogs, but more research was needed. The aim of this research project was therefore to have a better insight into the origin of this immunological problem. Blood was collected from litters of Wetterhoun dogs and was researched for abnormalities that could help find clues about the background of this disease. The hematology profile of the affected dogs showed a strong decrease in the lymphocyte numbers. The serum analysis for immunoglobulins IgA, IgM, IgG1 and IgG2 was done and showed almost no detectable immunoglobulins in the affected dogs. Furthermore the FACS result showed that almost no T and B cells where present in the blood of the affected pups and the pathology reports suggested a very severe kind of immunodeficiency in which both T and B cells where absent. These results strongly indicate that these dogs are dealing with Severe Combined Imunodeficiency Disease (SCID). The immunological tests make a SCID diagnosis at an early stage possible but this still leaves the question of the immunological and molecular origin of the immunodeficiency disease. To prevent the birth of affected pups in the future, further genetic research is needed. All different forms of SCID in other dogs and humans, with a matching hematology and immunoglobulin profile, form good candidates for this genetic research. But because in dogs only one autosomal form of SCID has been described, this type of SCID is a legitimate first candidate to start the genetic research. In this form of SCID, which exists in the Jack Russel terrier, a mutation in the DNA-PKcs gene disrupts the VDJ recombination that is responsible for the gene rearrangement of the highly polymorphic antigen-recognition regions of the lymphocytes. This results in a block of the development of the T and B cells in the pro-lymphocyte stage. But the other proteins operative in the VDJ recombination are also good candidates. These are Ku70, Ku80, artemis, XRCC4, RAG 1, RAG 2 and DNA Ligase IV. Furthermore SCID due to a defect in the adenosine deaminase (ADA) also causes comparable abnormalities in serum and blood. ADA should therefore also be considered as a candidate.