title: SCID in Jack Russell terriers: a new animal model of DNA-PKcs deficiency.
abstract: We recently described the incidence of a SCID disease in a litter of Jack Russell terriers. In this study, we show that the molecular defect in these animals is faulty V(D)J recombination. Furthermore, we document a complete deficit in DNA-dependent protein kinase activity that can be explained by a marked diminution in the expression of the catalytic subunit DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We conclude that as is the case in C.B-17 SCID mice and in Arabian SCID foals, the defective factor in these SCID puppies is DNA-PKcs. In mice, it has been clearly established that DNA-PKcs deficiency produces an incomplete block in V(D)J recombination, resulting in "leaky" coding joint formation and only a modest defect in signal end ligation. In contrast, DNA-PKcs deficiency in horses profoundly blocks both coding and signal end joining. Here, we show that although DNA-PKcs deficiency in canine lymphocytes results in a block in both coding and signal end joining, the deficit in both is intermediate between that seen in SCID mice and SCID foals. These data demonstrate significant species variation in the absolute necessity for DNA-PKcs during V(D)J recombination. Furthermore, the severity of the V(D)J recombination deficits in these three examples of genetic DNA-PKcs deficiency inversely correlates with the relative DNA-PK enzymatic activity expressed in normal fibroblasts derived from these three species.
authors.affiliation: College of Veterinary Medicine and Department of Veterinary Pathology, Michigan State University, East Lansing, MI 48824, USA. kmeek@msu.edu
authors.forename: K
authors.initials: K
authors.lastname: Meek
authors.forename: L
authors.initials: L
authors.lastname: Kienker
authors.forename: C
authors.initials: C
authors.lastname: Dallas
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: M J
authors.initials: MJ
authors.lastname: Dark
authors.forename: P J
authors.initials: PJ
authors.lastname: Venta
authors.forename: M L
authors.initials: ML
authors.lastname: Huie
authors.forename: R
authors.initials: R
authors.lastname: Hirschhorn
authors.forename: T
authors.initials: T
authors.lastname: Bell
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain / Q000235:genetics*; D002460:Cell Line; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000201:enzymology* / Q000235:genetics* / Q000276:immunology; D004285:Dogs; D005347:Fibroblasts / Q000276:immunology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000276:immunology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D011685:Purine Nucleotides / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry; D011995:Recombination, Genetic / Q000276:immunology / Q000528:radiation effects; D016511:Severe Combined Immunodeficiency / Q000201:enzymology* / Q000235:genetics* / Q000662:veterinary; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000201:enzymology
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011685:Purine Nucleotides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases