An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity

Ravindra Majeti, Zheng Xu, Tristram G. Parslow, Jean L. Olson, David I. Daikh, Nigel Killeen, Arthur Weiss

Research output: Contribution to journalArticlepeer-review

214 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1059-1070
Number of pages12
JournalCell
Volume103
Issue number7
DOIs
StatePublished - Dec 22 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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