title: Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency.
abstract: Four transacting genes, CIITA, RFXANK, RFX5, and RFXAP, control coordinate MHC II expression. In humans, defects in these genes result in the absence of MHC II expression and thus a combined immunodeficiency. CIITA is considered to be a master MHC II regulator and is responsible for the defect in complementation group A. Eight such affected families have been reported. We investigated the molecular basis of the defect in three patients in these families, all presenting a severe immunodeficiency. CIITA transcripts were detected in all three patients but in one at an abnormally low level. Three novel heterozygous mutations of CIITA were found in patients SP and RC. One SP CIITA allele contained a nonsense mutation, G2178A, leading to a premature stop codon and the other allele in SP was found not to be expressed. In patient RC, two in-frame deletions were detected: one of the nucleotides 3003-3084 corresponding to the exon coding from Leu(964)to Asp(991), in the paternal allele, and a CATdel3193-5 of the isoleucine codon at position 1027, in the maternal allele. Transfection of a CIITA-deficient cell line with the recombinant CATdel3193-5-CIITA cDNA revealed a loss of function for this mutant and retention of the protein in the cytoplasm. No mutations were detected in the 4.5-kb cDNA from patient OK but the level of CIITA transcript was found to be profoundly decreased. However, promoters III and IV were not affected. This last case represents the first described CIITA dysfunction due to putative mutation(s) in cis regulatory sequences of CIITA.
authors.affiliation: INSERM U429, Institut National de la Santé et le Recherche Médicale, Hôpital Necker, 119 rue de Serres, 75015 Paris, France.
authors.forename: Magda
authors.initials: M
authors.lastname: Dziembowska
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fondaneche
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Vedrenne
authors.forename: Giovanna
authors.initials: G
authors.lastname: Barbieri
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cant
authors.forename: Viktor
authors.initials: V
authors.lastname: Steimle
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.forename: Catherine
authors.initials: C
authors.lastname: Alca-Loridan
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Barbara
authors.initials: B
authors.lastname: Lisowska-Grospierre
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D050856:Interferon Regulatory Factor-1; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D015534:Trans-Activators