Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation.
Artemis is a mammalian protein, the absence of which results in SCID in Athabascan-speaking Native Americans (SCIDA). This novel protein has been implicated in DNA double-strand break repair and V(D)J recombination. We have cloned the Artemis murine counterpart, mArt, and generated a mouse with a targeted disruption of mArt. Artemis-deficient mice show a similar T-B- NK+ immunodeficiency phenotype, and carry a profound impairment in coding joint rearrangement, while retaining intact signal ends and close to normal signal joint formation. mArt-/- embryonic fibroblasts show increased sensitivity to ionizing radiation. Hemopoietic stem cell (HSC) transplantation using 500-5000 enriched congenic, but not allogeneic mismatched HSC corrected the T cell and partially corrected the B cell defect. Large numbers (40,000) of allogeneic mismatched HSC or pretreatment with 300 cGy of radiation overcame graft resistance, resulting in limited B cell engraftment. Our results suggest that the V(D)J and DNA repair defects seen in this mArt-/- mouse model are comparable to those in humans with Artemis deficiency, and that the recovery of immunity following HSC transplantation favors T rather than B cell reconstitution, consistent with what is seen in children with this form of SCID.
Li
Lanying
L
Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
Salido
Eduardo
E
Zhou
Yungui
Y
Bhattacharyya
Swati
S
Yannone
Steven M
SM
Dunn
Elizabeth
E
Meneses
Juanito
J
Feeney
Ann J
AJ
Cowan
Morton J
MJ
D000818:Animals; D000916:Antibody Diversity / Q000235:genetics / Q000528:radiation effects; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics* / Q000528:radiation effects; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics* / Q000528:radiation effects; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007133:Immunoglobulin Joining Region / Q000235:genetics / Q000528:radiation effects; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011836:Radiation Tolerance / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D014161:Transduction, Genetic
D004268:DNA-Binding Proteins; D007127:Immunoglobulin Constant Regions; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D009687:Nuclear Proteins; D011948:Receptors, Antigen, T-Cell; C426344:DCLRE1C protein, human; D004720:Endonucleases; C473337:Dclre1c protein, mouse