A defect in the nuclear translocation of CIITA causes a form of type II bare lymphocyte syndrome

The severe immunodeficiency type II bare lymphocyte syndrome (BLS) lacks cl ass II MHC gene transcription. One defect from a complementation group A ty pe II BLS patient is a 24 aa deletion in the MHC class II transactivator (C IITA). We show here that the molecular defect present in this protein is a failure of CIITA to undergo nuclear translocation. This defect was mapped t o a position-dependent, novel nuclear localization sequence that cannot be functionally replaced by a classical NLS. Fusion of this 5 aa motif to an u nrelated protein leads to nuclear translocation. Furthermore, this motif is not critical for transactivation function. This is a description of a gene tic disease resulting from a novel defect in the subcellular localization o f a transcriptional coactivator.