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

Corthals, G.
Aebersold, R.
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Published in Nature Genetics. 1998, vol. 20, no. 3, p. 273-277
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 multigene 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 genes. There are four genetic complementation groups (A, B, C and D), reflecting the existence of four MHC-II regulators. The factors defective in groups A (CIITA), C (RFX5) and D (RFXAP) have been identified. CIITA is a non-DNA-binding co-activator that controls the cell-type specificity and inducibility of MHC-II expression. RFX5 and RFXAP are two subunits of RFX, a multi-protein complex that binds the X box motif of MHC-II promoters. Mutations in the genes encoding RFX5 (RFX5) or RFXAP (RFXAP) abolish binding of RFX (refs 7,8,12). Similar to groups C and D, group B is characterized by a defect in RFX binding, 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.
Keywords Amino Acid SequenceBase SequenceDNA, Complementary/geneticsDNA-Binding Proteins/chemistry/ genetics/metabolismFemaleGenes, MHC Class IIHistocompatibility Antigens Class II/ metabolismHumansMaleMolecular Sequence DataMutationPedigreePromoter Regions, GeneticSequence Homology, Amino AcidTrans-Activators/chemistry/ genetics/metabolismTranscription Factors/chemistry/ genetics/metabolism
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PMID: 9806546
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