TY - JOUR
T1 - An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity
AU - Majeti, Ravindra
AU - Xu, Zheng
AU - Parslow, Tristram G.
AU - Olson, Jean L.
AU - Daikh, David I.
AU - Killeen, Nigel
AU - Weiss, Arthur
N1 - Funding Information:
We thank Linda Zuckerman for assistance with ES cell techniques, Scott Cogan for assistance with histological analysis, Louis Reichardt for use of microscopy equipment, Asta Saulys for assistance with mice husbandry, Jason Cyster for critical reading of this manuscript, and members of the Weiss lab for discussion and assistance. This work was supported by the Howard Hughes Medical Institute and NIH grant RO1-GM39553 (to A.W.). R. M. is supported by the NIH Medical Scientist Training Program.
PY - 2000/12/22
Y1 - 2000/12/22
N2 - A model has been proposed for the regulation of CD45, and by homology other RPTPs, in which dimerization inhibits phosphatase activity through symmetrical interactions between an inhibitory structural wedge and the catalytic site. Here, we report the phenotype of mice with a single point mutation, glutamate 613 to arginine, that inactivates the inhibitory wedge of CD45. The CD45 E613R mutation causes polyclonal lymphocyte activation leading to lymphoproliferation and severe autoimmune nephritis with autoantibody production, resulting in death. Both homozygotes and heterozygotes develop pathology, indicating genetic dominance of CD45 E613R. The dramatic phenotype of CD45 E613R mice demonstrates the in vivo importance of negative regulation of CD45 by dimerization, supporting the model for regulation of CD45, and RPTPs in general.
AB - A model has been proposed for the regulation of CD45, and by homology other RPTPs, in which dimerization inhibits phosphatase activity through symmetrical interactions between an inhibitory structural wedge and the catalytic site. Here, we report the phenotype of mice with a single point mutation, glutamate 613 to arginine, that inactivates the inhibitory wedge of CD45. The CD45 E613R mutation causes polyclonal lymphocyte activation leading to lymphoproliferation and severe autoimmune nephritis with autoantibody production, resulting in death. Both homozygotes and heterozygotes develop pathology, indicating genetic dominance of CD45 E613R. The dramatic phenotype of CD45 E613R mice demonstrates the in vivo importance of negative regulation of CD45 by dimerization, supporting the model for regulation of CD45, and RPTPs in general.
UR - http://www.scopus.com/inward/record.url?scp=0034704180&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034704180&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(00)00209-9
DO - 10.1016/S0092-8674(00)00209-9
M3 - Article
C2 - 11163182
AN - SCOPUS:0034704180
SN - 0092-8674
VL - 103
SP - 1059
EP - 1070
JO - Cell
JF - Cell
IS - 7
ER -