title: RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency.
abstract: Major Histocompatibility Complex class II (MHC-II) deficiency is a disease of gene regulation that provides a unique opportunity for the genetic 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 reflect the existence of distinct essential MHC-II regulatory genes. Groups B and C, as well as an in vitro generated regulatory mutant representing a fourth group (D), are characterized by a specific defect in the binding activity of RFX, a multimeric DNA binding complex that is essential 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 of 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. Complementation of the 6.1.6 and DA cell lines by transfection with RFXAP fully restores expression of all endogenous MHC-II genes in vivo, demonstrating that RFXAP is a novel essential MHC-II regulatory gene.
authors.affiliation: Department of Genetics and Microbiology, University of Geneva Medical School, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Durand
authors.forename: P
authors.initials: P
authors.lastname: Sperisen
authors.forename: P
authors.initials: P
authors.lastname: Emery
authors.forename: E
authors.initials: E
authors.lastname: Barras
authors.forename: M
authors.initials: M
authors.lastname: Zufferey
authors.forename: B
authors.initials: B
authors.lastname: Mach
authors.forename: W
authors.initials: W
authors.lastname: Reith
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics; D005802:Genes, MHC Class II / Q000235:genetics*; D005816:Genetic Complementation Test; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D000071701:Regulatory Factor X Transcription Factors; D017421:Sequence Analysis; D016511:Severe Combined Immunodeficiency / Q000235:genetics*; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D014170:Transformation, Genetic / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C093524:RFX5 protein, human; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D004247:DNA