October 30, 2017

SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a subunit of an enzyme crucial in DNA repair. Deficiencies in DNA-PK are lethal because vertebrate immune systems need a pathway in which the DNA-PK functions in order to complete V(D)J combination. Y(D)J recombination is the process that leads to proper lymphocyte development. Therefore, a deficiency in DNA-PK results in faulty V(D)J recombination and consequently a profound deficiency of mature B and T lymphocytes and the disease SCID. In previous studies done on SCID mice and SCID Arabian foals, scientists have determined that faulty V(D)J recombination, as a result of DNA-PKcs deficiency, is the defective factor producing SCID phenotypes in these animals. In mice, the DNA-PKcs deficiency produces only an incomplete block in V(D)J recombination and therefore only a “leaky” coding joint. In SCID Arabian foals, the deficiency results in blocked coding and signal end joining, which results in a more severe phenotype in foals than in mice.

 After 12 of 32 siblings in a single breeding pair litter of Jack Russell terriers came down with opportunistic infections within 8-14 weeks of birth, researchers began studying Jack Russells for DNA-PKcs deficiencies. They produced another litter from the same breeding pair to study the possible genetic immunodeficiency. In the second litter, the determined that 4 of 7 puppies displayed SCID phenotype (including lymphopenia, agammaglobulinemia, thymic dysplasia, peripheral lymphoid aplasia) and apparent autosomal recessive inheritance. With assess cell and tissue samples from these puppies, they determined that the immunodeficiency in the dogs was a result of defective V(D)J recombination which can be explained by DNA-PKcs deficiency. The coding and signal end joining were both impaired in the dogs, like they were in the SCID foals, but to a lesser degree. Therefore, the degree to which the SCID dogs are impaired is lesser than foals, but still greater than mice.

The differences in recombination defects found among dogs, mice, and foals (all as a result of DNA-PKcs deficiencies) show that the necessity for DNA-PKcs in V(D)J recombination varies among species. This is thought to be a result of how much DNA-PK enzymes are expressed normally in each type of animal.

Meek et el. SCID in Jack Russell Terriers: A New Animal Model of DNA-PKcs Deficiency. The Journal of Immunology, 167:2142-2150.

Original Article:

http://www.jimmunol.org/content/jimmunol/167/4/2142.full.pdf

Reviewed by: Katie Snodgrass