A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients

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Abstract
Major histocompatibility class II (MHC-II) molecules are transmembrane proteins that have a central role in development and control of the immune system. They are encoded by a multi-gene family and their expression is tightly regulated. MHC-II deficiency (OMIM 209920) is an autosomal recessive immunodeficiency syndrome resulting from defects in trans-acting factors essential for transcription of MHC-II genes1,2. There are four genetic complementation groups3,4,5 (A, B, C and D), reflecting the existence of four MHC-II regulators2. The factors defective in groups A (CIITA), C (RFX5) and D (RFXAP) have been identified6,7,8. CIITA is a non-DNA-binding co-activator that controls the cell-type specificity and inducibility of MHC-II expression6,9. RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters10,11. Mutations in the genes encoding RFX5 (RFX5) or RFXAP (RFXAP) abolish binding of RFX (Refs 7,12). Similar to groups C and D, group B is characterized by a defect in RFX binding2,10,11, and although it accounts for the majority of patients, the factor defective in group B has remained unknown. We report here the isolation of RFX by a novel single-step DNA-affinity purification approach and the identification of RFXANK, the gene encoding a third subunit of RFX. RFXANK restores MHC-II expression in cell lines from patients in group B and is mutated in these patients. RFXANK contains a protein-protein interaction region consisting of three ankyrin repeats. Its interaction with RFX5 and RFXAP is essential for binding of the RFX complex to MHC-II promoters.