A Gene Encoding a Novel RFX-associated Transactivator Is Mutated in the Majority of MHC Class II Deficiency Patients

Nat Genet. 1998 Nov;20(3):273-7. doi: 10.1038/3081.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • DNA, Complementary / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Female
  • Genes, MHC Class II
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Promoter Regions, Genetic
  • Regulatory Factor X Transcription Factors
  • Sequence Homology, Amino Acid
  • Trans-Activators / chemistry
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • DNA, Complementary
  • DNA-Binding Proteins
  • Histocompatibility Antigens Class II
  • Regulatory Factor X Transcription Factors
  • Trans-Activators
  • Transcription Factors

Associated data

  • GENBANK/AA118335
  • GENBANK/AA146531
  • GENBANK/AA205305
  • GENBANK/AA245178
  • GENBANK/AA259432
  • GENBANK/AA282432
  • GENBANK/AA290933
  • GENBANK/AA411028
  • GENBANK/AA418029
  • GENBANK/AA418089
  • GENBANK/AA435121
  • GENBANK/AA442702
  • GENBANK/AA496038
  • GENBANK/AA496321
  • GENBANK/AA616119
  • GENBANK/AA633452
  • GENBANK/AC003110
  • GENBANK/AD000812
  • GENBANK/AF094760
  • GENBANK/AF094761
  • GENBANK/H39858
  • GENBANK/H63462
  • GENBANK/N25678
  • GENBANK/N55216
  • GENBANK/N64316
  • GENBANK/N70046
  • GENBANK/R63682
  • GENBANK/R86213
  • GENBANK/Z31339