Deficiency of Janus family 3 (Jak3) tryosine kinase has recently been demonstrated to result in human SCID, a condition characterized by the absence of T and NK cells and non-functional B-cell signaling and to define functionally important regions of the Jak3 molecule by analysis of mutant Jak3 proteins in affected SCID human. The P1 hypothesizes that Jak3 is not required for all IL-4 signaling events and, therefore, plans to examine IL-4 induced activation of the Stat6 protein, IRS-1, and pi3-kinase in EBV-transformed B-cell lines and fresh peripheral book B-cells from Jak3 molecule, particularyly in cases exhibiting mutations that permit protein expression. For Jak3 mutation detection in these studies, he will use SSCP and dideoxy fingerprinting in conjunction with standard sequencing of suspect regions. He also hypothesize that some Jak3 mutations will result in attenuated immune deficits manifest as combined immunodeficiency (CID) or common variable immunodeficiency (CVID). This theory will be tested by examining Jak3 protein expression and functionin select CID and CVID patients. Structure/function analysis of expressed mutant Jak3 proteins in such patients will likely prove particularly informative. The health relevance of this project is underscored by the fact that Jak3 deficiency causes at least 5 percent of human SCID. It is, therefore, of great intrest to determine the precise role Jak3 plays in lymphocyte signaling and to pinpoint functionally important regions of the Jak3 molecule.
| Roberts, Joseph L; Lauritsen, Jens Peter H; Cooney, Myriah et al. (2007) T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3zeta subunit of the T-cell antigen receptor complex. Blood 109:3198-206 |
| Roberts, Joseph L; Lengi, Andrea; Brown, Stephanie M et al. (2004) Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood 103:2009-18 |
