RFXAP, A NOVEL SUBUNIT OF THE RFX DNA-BINDING COMPLEX IS MUTATED IN MHC CLASS-II DEFICIENCY

Major Histocompatibility Complex class II (MHC-II) deficiency is a dis ease of gene regulation that provides a unique opportunity for the gen etic dissection of the molecular mechanisms controlling transcription of MHC-II genes. Cell lines from MHC-II deficiency patients have been assigned to three complementation groups (A, B and C) believed to refl ect the existence of distinct essential MRC-II regulatory genes. Group s B and C, as well as an in vitro generated regulatory mutant represen ting a fourth group (D), are characterized by a specific defect in the binding activity of RFX, a multimeric DNA binding complex that is ess ential for activation of MHC-II promoters. RFX5, a subunit of RFX, was recently shown to be mutated in group C. We have now isolated a novel gene, RFXAP (RFX Associated Protein), that encodes a second subunit o f the RFX complex, RFXAP is mutated in the 6.1.6 cell line (group D), as well as in an MHC-II deficiency patient (DA). This establishes that group D is indeed a fourth MHC-II deficiency complementation group. C omplementation of the 6.1.6 and DA cell lines by transfection with RFX AP fully restores expression of all endogenous MHC-II genes in vivo, d emonstrating that RFXAP is a novel essential MHC-II regulatory gene.