Vet Pathol Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Perryman, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Perryman, L. E.
Vet Pathol 41:95-100 (2004)
© 2004 American College of Veterinary Pathologists
ANIMAL MODELS

Molecular Pathology of Severe Combined Immunodeficiency in Mice, Horses, and Dogs

L. E. Perryman

College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO


   Abstract
Top
 Abstract
Molecular Requirements for...
 SCID in Mice
 SCID in Horses
 SCID in Dogs
 References
 
Severe combined immunodeficiency (SCID) is an inherited disorder of humans, mice, horses, and dogs, in which affected individuals are incapable of generating antigen-specific immune responses. It occurs when lymphocyte precursors fail to differentiate into mature lymphocytes because of mutations within recom binase-activating genes 1 and 2 or within the genes encoding deoxyribonucleic acid (DNA)–dependent protein kinase (DNA-PK). It also occurs when differentiated lymphocytes are incapable of completing signal transduction pathways because of defects in cell surface receptors for interleukins (IL). A spontaneous mutation in DNA-PKcs of BALB/c mice results in SCID, as do experimentally induced mutations in RAG1 and RAG2. SCID in horses results from a spontaneous mutation in DNA-PKcs. Two molecular mechanisms account for SCID in dogs. Jack Russell Terriers have a mutation within the DNA-PKcs gene, whereas Cardigan Welsh Corgi and Basset Hound have different defects in the gene encoding the {gamma} chain that is common to the receptors for IL-2, -4, -7, -9, -15, and -21. The location of the mutation within target genes influences the spectrum of diseases observed in affected animals.

Key words: DNA-dependent protein kinase; dogs; horses; interleukin receptors; mice; molecular pathology; recombinase-activating genes; severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is an inherited disorder of humans, mice, horses, and dogs, in which affected individuals are incapable of generating antigen-specific immune responses sufficient to protect them from infectious diseases. The disorder was first described in children during the 1960s and may result from molecular defects in at least 15 different enzymes or other proteins required for lymphocyte differentiation or signal transduction.44 Inheritance may be autosomal recessive, X-linked, or sporadic, depending on the molecular defect in affected persons.

The first spontaneous animal counterpart of SCID was described in horses in 1973.24 The disorder is limited to horses of the Arabian breed and is inherited as an autosomal recessive trait.33 In 1983, SCID was described in C.B-17 BALB/c mice in which the disease is also inherited as an autosomal recessive disorder.6 SCID was subsequently described in three breeds of dogs—Basset Hound (X-linked inheritance), Cardigan Welsh Corgi, and Jack Russell Terriers (autosomal recessive inheritance).2,21,46 The spontaneously occurring molecular defects in mice, horses, and dogs have been defined and offer clues to the disease patterns observed in affected animals.


   Molecular Requirements for Lymphocyte Differentiation
Top
 Abstract
 Molecular Requirements for...
SCID in Mice
 SCID in Horses
 SCID in Dogs
 References
 
The differentiation of mature T- and B lymphocytes from lymphoid precursors requires the rearrangement and expression of genes encoding T-cell receptors and immunoglobulin receptors, respectively. Gene segments encoding Variable (V), Diversity (D), and Joining (J) proteins must be rearranged and brought into proximity for successful transcription and translation. Two groups of enzymes are critical to the success of these gene rearrangement events (Fig. 1). Recombinase-activating genes 1 and 2 (RAG1, and RAG2) are expressed only in lymphoid tissues, whereas the deoxyribonucleic acid (DNA)–dependent protein kinase (DNA-PK) gene family is expressed in virtually all tissues. The RAG and DNA-PK gene products act sequentially within T- and B-lymphocyte precursors to cut, rearrange, and anneal DNA that encodes T-lymphocyte antigen-specific receptors and B-lymphocyte surface immunoglobulin receptors, respectively. Failure to properly complete these gene rearrangement events results in the elimination of lymphocyte precursors and near absence of mature, functional T- and B lymphocytes. RAG-1 and RAG-2 make the initial cuts in DNA required for ultimate rearrangement of T-cell receptor and B-cell surface immunoglobulin receptors. Defects in RAG1 and RAG2 genes cause SCID in children.38,39 Spontaneous mutations in RAG1 and RAG2 have not been described in species other than humans. However, mice engineered to express RAG1 and RAG2 mutant genes develop non–T, non–B SCID similar to that observed in children with RAG-1 or RAG-2 deficiencies.28,43



View larger version (25K):
[in this window]
[in a new window]
  		Fig. 1. The sequential action of RAG 1, RAG 2, and DNA-PK completes V(D)J recombination required for transcription and translation of T-lymphocyte receptors and B-lymphocyte surface immunoglobulin receptors.

 
DNA-PK is believed to play an important role in DNA repair. Within lymphocyte precursors, DNA-PK acts after RAG-1 and RAG-2 and anneals severed DNA to produce genes that encode the antigen-specific T-cell receptors and surface immunoglobulin receptors characteristic of functionally mature lymphocytes. During the annealing process, coding joints and signal joints are formed. The signal joints are formed when intervening regions of DNA are excised and circularized during V(D)J recombination. The coding joints between V and (D) regions, as well as between (D) and J regions, are directly involved in antigen binding by B-lymphocyte surface immunoglobulin receptors and T-lymphocyte receptors.

DNA-PK has three subunits, the molecular mass of which varies among animal species (Fig. 2). The Ku portion of DNA-PK has two subunits with molecular masses of approximately 80 and 70 kd. The larger subunit (p80) binds to the free ends of double-stranded DNA in a sequence-independent manner. The DNA-PK catalytic subunit (DNA-PKcs) joins Ku after p80 has bound to double-stranded DNA. DNA-PK becomes a functional kinase in this configuration, adding phosphate groups to several acceptor proteins. As described below, mutations interfering with DNA-PK in C.B-17 mice, foals, and Jack Russell Terriers occur in DNA-PKcs, and proper function of DNA-PK is essential for the formation of coding joints during V(D)J gene rearrangement events. DNA-PK is essential for signal joint formation in horses but not in mice or dogs.14



View larger version (20K):
[in this window]
[in a new window]
  		Fig. 2. Subcomponents of DNA-dependent protein kinase.

 
T- and B-lymphocyte precursors that successfully complete V(D)J recombination and migrate to peripheral lymphoid tissues communicate through the release and binding of proteins collectively referred to as interleukins (IL). Interactions between IL and responsive cells occur only through specific IL receptors that are often composed of multiple proteins. Receptors for IL-2, -4, -7, -9, -15, and -21 are able to distinguish among and specifically bind their requisite ILs. However, the receptors for IL-2, -4, -7, -9, -15, and -21 contain a {gamma} chain common to all six receptors.35,47 The {gamma}c is essential for lymphokine-dependent signal transduction. Mutations in the gene encoding {gamma}c are responsible for most X-linked SCID in children, and numerous mutations impairing {gamma}c production and function have been documented.35 Two breeds of dogs (described below) develop SCID because of mutations in {gamma}c.


   SCID in Mice
Top
 Abstract
 Molecular Requirements for...
 SCID in Mice
SCID in Horses
 SCID in Dogs
 References
 
SCID was described in C.B-17 mice on BALB/c background in 1983.6 The disorder is inherited as an autosomal recessive trait and results in the near absence of mature T- and B lymphocytes (non–T, non–B SCID).10 Affected mice are remarkably susceptible to bacterial, viral, fungal, and protozoal infections because of their inability to generate antigen-specific immune responses. However, the life span of immunodeficient mice can be extended beyond 1 year through proper management that minimizes exposure of these mice to infectious agents. Under such conditions, some SCID mice produce immunoglobulins beginning at 6 months of age, and virtually all are "leaky" by 10–14 months of age.8–10,12 The term "leaky SCID" has been used to describe the phenomenon by which affected mice produce some immunoglobulins and lymphocytes with markers characteristic of T cells. T-cell lymphomas in the thymus were reported in 41 of 269 (15%) SCID mice 10–65 weeks of age.13

Cells from SCID mice are highly susceptible to ionizing radiation, suggesting reduced ability to repair DNA defects. SCID mice also lack DNA-PK enzyme activity.4,22 Further studies showed that the Ku component of DNA-PK was present, and that DNA-PK activity was restored by addition of functional DNA-PKcs.4 The gene encoding DNA-PKcs, located on chromosome 16, was sequenced, and a single nucleotide substitution, resulting in a premature stop codon, was revealed.5,7 The mutation prevents translation of the 83 C-terminal amino acids of DNA-PKcs and substantially reduces DNA-PK enzyme activity.5 Coding joint formation occurs poorly, if at all, in mice deficient in DNA-PK activity, but signal joint formation proceeds normally.29,37 This suggested that DNA-PKcs does not participate in signal joint formation, or that mice possess redundant pathways for completing this reaction. It now appears that the latter explanation is correct, and that murine RAG-1 and RAG-2 can catalyze signal joint formation in the absence of DNA-PK activity.27,42

The molecular basis of leaky SCID is not known. The C-terminal sequence of DNA-PKcs shares remarkable homology with that of phosphatidylinositol-3-kinase.19,34,40 By analogy to the known structure and function of phosphatidylinositol-3-kinase, truncation of DNA-PKcs 83 amino acids before the C terminus does not eliminate the full active site of the enzyme (Fig. 3). Reading through the premature ochre stop codon in SCID mice over 6 months of age may provide sufficient stable DNA-PKcs to catalyze coding joint formation, with subsequent immunoglobulin production and T-lymphocyte proliferation.5



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 3. Comparison of the SCID mutations in DNA-PKcs from mice, dogs, and horses. The unmutated human DNA-PKcs contains 4,127 amino acids, of which the 325 C-terminal amino acids are homologous to phosphatidylinositol-3-kinase (PI3K).19,34. PI3K contains three subdomains, and the active site of the enzyme is within subdomain 2. DNA-PKcs gene mutations in SCID mice, dogs, and horses prevent translation of the C-terminal 83, 517, and 967 amino acids, respectively.

 

   SCID in Horses
Top
 Abstract
 Molecular Requirements for...
 SCID in Mice
 SCID in Horses
SCID in Dogs
 References
 
SCID was first described in two foals in 1973 and is known to be an autosomal recessive disorder limited to horses of the Arabian breed.24,25,33 The paucity of mature T and B lymphocytes in affected Arabian foals is profound. These foals produce no antibodies after infection or immunization, and no evidence of leakiness has been detected.18,23,30,31 SCID foals rarely survive up to 5 months of age before succumbing to infections caused by equine adenovirus, Pneumocystis carinii, Cryptosporidium parvum, or many species of bacteria.3,32,45 Like SCID mice, the immunologic defects in SCID foals can be corrected through transplantation of normal histocompatible bone marrow cells.11,31

Fibroblasts from SCID foals are more susceptible to the lethal effects of ionizing radiation, suggesting a defect in DNA repair systems.48 Based on this observation, and the knowledge that SCID mice lack DNA-PK activity, we showed that SCID foals also lack this enzyme activity.48 Equine DNA-PKcs is located on chromosome 9.1 Cells from SCID foals contain Ku that is able to bind double-stranded DNA but lack detectable DNA-PKcs protein.48 Sequence analysis of the equine DNA-PKcs revealed a five–base pair deletion, resulting in a frame-shift mutation and premature stop codon.40 The mutation prevented translation of the 967 C-terminal amino acids, resulting in a nonstable protein.40,48 By analogy to phosphatidylinositol-3-kinase, absence of the 967 C-terminal amino acids of DNA-PKcs eliminates the active site of DNA-PK (Fig. 3). SCID foals are incapable of V(D)J gene rearrangement for immunoglobulin heavy chains and T-cell receptors.42 Neither coding joints nor signal joints are formed in SCID foals.48 Therefore, in contrast to mice, DNA-PK is required for signal joint formation in horses. This suggests that horses lack redundant pathways for catalyzing signal joint reactions.

Neoplasia is uncommon in horses below 8 years of age, and SCID foals rarely survive up to 5 months of age. Therefore, it is not surprising that neoplasms have not been described in SCID foals. However, horses heterozygous for the SCID trait are at greater risk for developing sarcoids, suggesting that DNA-PK may function as a tumor suppressor through its ability to repair DNA.14 The existence of a heterozygote detection assay makes it possible to reduce the frequency of the DNA-PKcs mutation through selective breeding.41


   SCID in Dogs
Top
 Abstract
 Molecular Requirements for...
 SCID in Mice
 SCID in Horses
 SCID in Dogs
References
 
Two distinct molecular mechanisms result in SCID in dogs. Recently, SCID was reported in Jack Russell Terriers and shown to be due to near absence of DNA-PK activity.2,26 A point mutation results in a premature stop codon at nucleotide 10,828 of DNA-PKcs and terminates translation of DNA-PKcs 517 amino acids before the C terminus.14 This loss of C-terminal amino acids from DNA-PKcs is intermediate between that reported for SCID in mice and SCID in foals (Fig. 3). Interestingly, impairment of signal joint formation is also intermediate between that reported for mice with SCID and foals with SCID.14 Jack Russell Terrier puppies with SCID succumb to infections at a few months of age. No evidence of neoplasia or leakiness has been reported.

Basset Hounds with SCID were first recognized in 1982, and the disorder was described as X-linked SCID in 1989.16,18,21 X-linked SCID is characterized by moderate lymphopenia, with normal percentages of circulating B lymphocytes and low to normal percentages of phenotypically mature, but nonfunctional, T lymphocytes. Dogs with X-linked SCID are able to complete the gene rearrangement events depicted in Fig. 1. Therefore, these dogs possess lymphocytes with surface markers characteristic of mature T- and B lymphocytes. Affected puppies are remarkably susceptible to bacterial and viral infections and rarely survive past 3–4 months of age when raised in conventional environments. These puppies are able to synthesize IgM so that their serum concentrations are similar to those of normal littermates.15 However, their serum IgG concentrations are significantly reduced, and IgA is typically not detectable. Affected puppies produce minimal quantities of specific antibodies after immunization with bacteriophage {Phi}X-174. Virtually all the antibody produced is of the IgM class, indicating inability to class-switch to IgG and IgA.15 One case of acute monocytic leukemia was reported in a dog with X-linked SCID that was maintained in a gnotobiotic environment to 20 months of age.17 After the characterization of this immunodeficiency disorder in the Basset Hound, a very similar manifestation of SCID was reported in puppies of the Cardigan Welsh Corgi.36,46

SCID in Basset and Cardigan Welsh Corgi puppies involves a mutation in the gene encoding the {gamma} chain of the IL-2 receptor (IL2RG). As mentioned, this {gamma} chain ({gamma}c) is common to the receptors for IL-2, -4, -7, -9, -15, and -21, and mutations within it prevent lymphocytes in affected dogs from completing signal transduction pathways initiated by any of these ILs.20 The canine IL2RG encodes a polypeptide 373 amino acids long.20 The mutation in Bassets involves the deletion of four base pairs (CCTC at positions 30–33) in exon 1. This results in a premature stop codon and in translation of a predicted polypeptide that is 21 amino acids long and contains only 10 amino acids of the normal polypeptide sequence. Interestingly, the corresponding messenger ribonucleic acid is readily detectable on northern blots and appears to be stable.20 In the Cardigan Welsh Corgi, insertion of a cytosine after nucleotide 582 in exon 4 results in a premature stop codon that also prevents full translation of {gamma}c.46

It is not surprising that different mutations of IL2RG occur in two breeds of dogs. Mutation of IL2RG is the most common molecular mechanism for SCID in children. The human IL2RG coding region contains 1,124 nucleotides and eight exons. More than 145 distinct point, insertion, and deletion mutations, involving all eight exons, have been reported.35

SCID in mice, horses, and dogs provides useful models for defining the molecular requirements for lymphocyte differentiation and function, the immunologic mechanisms of protection against infectious agents, and a venue for exploring treatments for immunodeficiency disorders in children. Investigation of other animals with apparent immunodeficiency disorders will likely reveal additional molecular mechanisms of comparative biomedical interest.


   Acknowledgments
 
I thank Dr. Gerald Callahan for helpful comments on the manuscript.


   References
Top
 Abstract
 Molecular Requirements for...
 SCID in Mice
 SCID in Horses
 SCID in Dogs
 References
 

  1. Bailey E, Reid RC, Skow LC, Mathiason K, Lear TL, McGuire TC: Linkage of the gene for equine combined immunodeficiency disease to microsatellite markers HTG8 and HTG4, synteny and FISH mapping to ECA9. Anim Genet 28:268-273, 1997[CrossRef][ISI][Medline]
  2. Bell TG, Butler KL, Stickle JE, Ramos-Vara JA, Dark MJ: Autosomal recessive severe combined immunodeficiency of Jack Russell terriers. J Vet Diagn Invest 14:194-204, 2002[Abstract/Free Full Text]
  3. Bjorneby JM, Leach DR, Perryman LE: Persistent cryptosporidiosis in horses with severe combined immunodeficiency. Infect Immun 59:3823-3826, 1991[Abstract/Free Full Text]
  4. Blunt T, Finnie NJ, Taccioli GE, Smith GC, Demengeot J, Gottleib TM, Mizuta R, Varghese AJ, Alt FW, Jeggo PA, Jackson SP: Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell 80:813-823, 1995[CrossRef][ISI][Medline]
  5. Blunt T, Gell D, Fox M, Taccioli GE, Lehmann AR, Jackson SP, Jeggo PA: Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc Natl Acad Sci 93:10285-10290, 1996[Abstract/Free Full Text]
  6. Bosma GC, Custer RP, Bosma MJ: A severe combined immunodeficiency mutation in the mouse. Nature 301:527-530, 1983[CrossRef][Medline]
  7. Bosma GC, Davisson MT, Ruetsch NR, Sweet HO, Shultz LD, Bosma MJ: The mouse mutation severe combined immunodeficiency (scid) is on chromosome 16. Immunogenetics 29:54-57, 1989[CrossRef][ISI][Medline]
  8. Bosma GC, Fried M, Custer RP, Carroll AM, Gibson DM, Bosma MJ: Evidence of functional lymphocytes in some (leaky) scid mice. J Exp Med 167:1016-1033, 1988[Abstract/Free Full Text]
  9. Bosma MJ: B and T cell leakiness in the scid mouse mutant. Immunodef Rev 3:261-276, 1992[Medline]
  10. Bosma MJ, Carroll AM: The scid mouse mutant: definition, characterization, and potential uses. Ann Rev Immunol 9:323-350, 1991[CrossRef][ISI][Medline]
  11. Bue CM, Davis WC, Magnuson NS, Mottironi VD, Ochs HD, Wyatt CR, Perryman LE: Correction of equine severe combined immunodeficiency by bone marrow transplantation. Transplantation 42:14-19, 1986[ISI][Medline]
  12. Carroll AM, Hardy RR, Petrini J, Bosma MJ: T cell leakiness in scid mice. Curr Top Microbiol Immunol 152:117-123, 1989[ISI][Medline]
  13. Custer RP, Bosma GC, Bosma MJ: Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol 120:464-477, 1985[Abstract]
  14. Ding Q, Bramble L, Yuzbasiyan-Gurkan V, Bell T, Meek K: DNA-PKcs mutations in dogs and horses: allele frequency and association with neoplasia. Gene 283:263-269, 2002[CrossRef][ISI][Medline]
  15. Felsburg PJ, Hartnett BJ, Henthorn PS, Moore PF, Krakowka S, Ochs HD: Canine X-linked severe combined immunodeficiency. Vet Immunol Immunopathol 69:127-135, 1999[CrossRef][ISI][Medline]
  16. Felsburg PJ, Jezyk PF: A canine model for variable, combined immunodeficiency. Clin Res 30:347-356, 1982
  17. Felsburg PJ, Somberg RL, Krakowka S: Acute monocytic leukemia in a dog with X-linked severe combined immunodeficiency. Clin Diagn Lab Immunol 1:379-384, 1994[Abstract/Free Full Text]
  18. Felsburg PJ, Somberg RL, Perryman LE: Domestic animal models of severe combined immunodeficiency: canine x-linked severe combined immunodeficiency and severe combined immunodeficiency in horses. Immunodef Rev 3:277-303, 1992[Medline]
  19. Hartley KO, Gell D, Smith GC, Zhang H, Divecha N, Connelly MA, Admon A, Lees-Miller SP, Anderson CW, Jackson SP: DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 82:849-856, 1995[CrossRef][ISI][Medline]
  20. Henthorn PS, Somberg RL, Fimiani VM, Puck JM, Patterson DF, Felsburg PJ: IL-2R{gamma} gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease. Genomics 23:69-74, 1994[CrossRef][ISI][Medline]
  21. Jezyk PF, Felsburg PJ, Haskins ME, Patterson DF: X-linked severe combined immunodeficiency in the dog. Clin Immunol Immunopathol 52:173-189, 1989[CrossRef][ISI][Medline]
  22. Kirchgessner CU, Patil CK, Evans JW, Cuomo CA, Fried LM, Carter L, Oettinger MA, Brown JM: DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science 267:1178-1183, 1995[Abstract/Free Full Text]
  23. McGuire TC, Banks KL, Poppie MJ: Combined immunodeficiency in horses: characterization of the lymphocyte defect. Clin Immunol Immunopathol 3:555-566, 1975[CrossRef][ISI][Medline]
  24. McGuire TC, Poppie MJ: Hypogammaglobulinemia and thymic hypoplasia in horses: a primary combined immunodeficiency disorder. Infect Immun 8:272-277, 1973[Abstract/Free Full Text]
  25. McGuire TC, Poppie MJ, Banks KL: Combined (B- and T-lymphocyte) immunodeficiency: a fatal genetic disease in Arabian foals. J Am Vet Med Assoc 164:70-76, 1974[ISI][Medline]
  26. Meek K, Kienker L, Dallas C, Wang W, Dark MJ, Venta PJ, Huie ML, Hirschhorn R, Bell T: SCID in Jack Russell terriers: a new animal model of DNA-PKcs deficiency. J Immunol 167:2142-2150, 2001[Abstract/Free Full Text]
  27. Melek M, Gellert M, van Gent DC: Rejoining of DNA by the RAG1 and RAG2 proteins. Science 280:301-303, 1998[Abstract/Free Full Text]
  28. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE: RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68:869-877, 1992[CrossRef][ISI][Medline]
  29. Nakajima PB, Bosma MJ: Variable diversity joining recombination: nonhairpin coding ends in thymocytes of SCID and wild-type mice. J Immunol 169:3094-3104, 2002[Abstract/Free Full Text]
  30. Perryman LE: Primary immunodeficiencies of horses. Vet Clin North Am Equine Pract 16:105-116, 2000[ISI][Medline]
  31. Perryman LE, Bue CM, Magnuson NS, Mottironi VD, Ochs HD, Wyatt CR: Immunologic reconstitution of foals with combined immunodeficiency. Vet Immunol Immunopathol 17:495-508, 1987[CrossRef][ISI][Medline]
  32. Perryman LE, McGuire TC, Crawford TB: Maintenance of foals with combined immunodeficiency: causes and control of secondary infections. Am J Vet Res 39:1161-1167, 1978[ISI][Medline]
  33. Perryman LE, Torbeck RL: Combined immunodeficiency of Arabian horses: confirmation of autosomal recessive mode of inheritance. J Am Vet Med Assoc 176:1250-1251, 1980[ISI][Medline]
  34. Poltoratsky VP, Shi X, York JD, Lieber MR, Carter TH: Human DNA-activated protein kinase (DNA-PK) is homologous to phosphatidylinositol kinases. J Immunol 155:4529-4533, 1995[Abstract]
  35. Puck JM: X-linked severe combined immunodeficiency. In: Primary Immunodeficiency Diseases. A Molecular and Genetic Approach, ed. Ochs HD, Smith CIE, and Puck JM, chap. 8, pp 99-110, Oxford University Press, New York, NY 1999
  36. Pullen RP, Somberg RL, Felsburg PJ, Henthorn PS: X-linked severe combined immunodeficiency in a family of Cardigan Welsh corgis. J Am Anim Hosp Assoc 33:494-499, 1997[Abstract]
  37. Schuler W, Weiler IJ, Schuler A, Phillips RA, Rosenberg N, Mak TW, Kearney JF, Perry RP, Bosma MJ: Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell 46:963-972, 1986[CrossRef][ISI][Medline]
  38. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Firedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, Lieber MR, Bartram CR: RAG mutations in human B cell-negative SCID. Science 274:97-99, 1996[Abstract/Free Full Text]
  39. Schwarz K, Notarangelo LD, Spanopoulou E, Vezzoni P, Villa A: Recombination defects. In: Primary Immunodeficiency Diseases. A Molecular and Genetic Approach, ed. Ochs HD, Smith CIE, and Puck JM, chap. 13, pp 155-166, Oxford University Press, New York, NY 1999
  40. Shin EK, Perryman LE, Meek K: A kinase negative mutation of DNA-PKCS in equine scid results in defective coding and signal joint formation. J Immunol 158:3565-3569, 1997[Abstract]
  41. Shin EK, Perryman LE, Meek K: Evaluation of a test for identification of Arabian horses heterozygous for the severe combined immunodeficiency trait. J Am Vet Med Assoc 211:1268-1270, 1997[ISI][Medline]
  42. Shin EK, Rijkers T, Pastink A, Meek K: Analyses of TCRB rearrangements substantiate a profound deficit in recombination signal sequence joining in SCID foals: implications for the role of DNA-dependent protein kinase in V(D)J recombination. J Immunol 164:1416-1424, 2000[Abstract/Free Full Text]
  43. Shinkai Y, Rathbun G, Lam K-P, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, Alt FW: RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68:855-867, 1992[CrossRef][ISI][Medline]
  44. Smith CIE, Ochs HD, Puck JM: Genetically determined immunodeficiency diseases: a perspective. In: Primary Immunodeficiency Disorders. A Molecular and Genetic Approach, ed. Ochs HD, Smith CIE, and Puck JM, chap. 1, pp 3-11, Oxford University Press, New York, NY 1999
  45. Snyder SP, England JJ, McChesney AE: Cryptosporidiosis in immunodeficient Arabian foals. Vet Pathol 15:12-17, 1978[Abstract]
  46. Somberg RL, Pullen RP, Casal ML, Patterson DF, Felsburg PJ, Henthorn PS: A single nucleotide insertion in the canine interleukin-2 receptor gamma chain results in X-linked severe combined immunodeficiency disease. Vet Immunol Immunopathol 47:203-213, 1995[CrossRef][ISI][Medline]
  47. Ueda C, Akasaka T, Kurata M, Maesako Y, Nishikori M, Ichinohasama R, Imada K, Uchiyama T, Ohno H: The gene for interleukin-21 receptor is the partner of BCL6 in t(3;16)(q27; p11), which is recurrently observed in diffuse large B-cell lymphoma. Oncogene 21:368-376, 2002[CrossRef][ISI][Medline]
  48. Wiler R, Leber R, Moore BB, VanDyk LE, Perryman LE, Meek K: Equine severe combined immunodeficiency: a defect in V(D)J recombination and DNA-dependent protein kinase activity. Proc Natl Acad Sci 92:11485-11489, 1995[Abstract/Free Full Text]
Request reprints from Dr. L. Perryman, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1601 (USA). E-mail: lance.perryman{at}colostate.edu.




This article has been cited by other articles:


Home page
 Mol. Cell. Biol.Home page
R. S. Maser, K.-K. Wong, E. Sahin, H. Xia, M. Naylor, H. M. Hedberg, S. E. Artandi, and R. A. DePinho
DNA-Dependent Protein Kinase Catalytic Subunit Is Not Required for Dysfunctional Telomere Fusion and Checkpoint Response in the Telomerase-Deficient Mouse
Mol. Cell. Biol., March 15, 2007; 27(6): 2253 - 2265.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
M. F. Cesta
Normal Structure, Function, and Histology of the Spleen
Toxicol Pathol, August 1, 2006; 34(5): 455 - 465.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
G. Pearse
Normal Structure, Function and Histology of the Thymus
Toxicol Pathol, August 1, 2006; 34(5): 504 - 514.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Perryman, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Perryman, L. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS