TY - JOUR
T1 - Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency
AU - Dziembowska, Magda
AU - Fondaneche, Marie Claude
AU - Vedrenne, Jocelyn
AU - Barbieri, Giovanna
AU - Wiszniewski, Wojciech
AU - Picard, Capucine
AU - Cant, Andrew J.
AU - Steimle, Viktor
AU - Charron, Dominique
AU - Alcaïde-Loridan, Catherine
AU - Fischer, Alain
AU - Lisowska-Grospierre, Barbara
N1 - Funding Information:
Acknowledgements The authors wish to thank E. Jouanguy, F. Le Deist, and F. Selz for their expert collaboration. This work was supported in part by the Progrès Program (INSERM) and by the Association pour la Recherche sur le Cancer. M.D. and W.W. are Ph.D. students of the Postgraduate School of Molecular Medicine at Warsaw Medical University. J.V. and G.B. were supported by grants from the Fondation pour la Recherche Médicale and Fond-ation de France, respectively. W.W. was the recipient of a Young Scientist Award from the Foundation for Polish Science.
PY - 2002
Y1 - 2002
N2 - 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 Leu964 to Asp991, in the paternal allele, and a CATde13193-5 of the isoleucine codon at position 1027, in the maternal allele. Transfection of a CIITA-deficient cell line with the recombinant CATde13193-5-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.
AB - 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 Leu964 to Asp991, in the paternal allele, and a CATde13193-5 of the isoleucine codon at position 1027, in the maternal allele. Transfection of a CIITA-deficient cell line with the recombinant CATde13193-5-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.
KW - CIITA
KW - Gene regulation
KW - HLA
KW - MHC class II deficiency
KW - MHC class II transactivator
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U2 - 10.1007/s00251-001-0395-7
DO - 10.1007/s00251-001-0395-7
M3 - Article
C2 - 11862382
AN - SCOPUS:18344391606
SN - 0093-7711
VL - 53
SP - 821
EP - 829
JO - Immunogenetics
JF - Immunogenetics
IS - 10-11
ER -