Uncoordinated HLA-D Gene Expression in a RFXANK-Defective Patient with MHC Class II Deficiency

• Published in: The Journal of immunology (1950) 2001-05, Vol.166 (9), p.5681-5687
• Main Authors: Lennon-Dumenil, Ana-Maria, Barbouche, Mohamed-Ridha, Vedrenne, Jocelyn, Prod'Homme, Thomas, Bejaoui, Mohamed, Ghariani, Salma, Charron, Dominique, Fellous, Marc, Dellagi, Koussay, Alcaide-Loridan, Catherine
• Format: Article
• Language: English
• Subjects: Alternative Splicing - genetics; Alternative Splicing - immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cell Line, Transformed; Female; Gene Expression Regulation - immunology; Genes, MHC Class II; Genetic Complementation Test; histocompatibility antigen HLA; HLA-D Antigens - biosynthesis; HLA-D Antigens - genetics; HLA-DQ alpha-Chains; HLA-DQ Antigens - biosynthesis; HLA-DQ Antigens - genetics; HLA-DR alpha-Chains; HLA-DR Antigens - biosynthesis; HLA-DR Antigens - genetics; Humans; Infant; Male; RFXANK gene; RNA, Messenger - biosynthesis; Sequence Deletion; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - immunology; Transcription Factors - biosynthesis; Transcription Factors - deficiency; Transcription Factors - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.9.5681

We describe the analysis of a patient, JER, presenting classical immunological features of MHC class II deficiency. Unexpectedly, some HLA transcripts (HLA-DRA, HLA-DQA, and HLA-DMA) were found to be expressed in the JER cell line at nearly wild-type levels, while HLA-DPA and the HLA-D beta-chain transcripts were not detected. Gene reporter experiments confirmed the differential transcriptional activities driven by the HLA-D promoters in the JER cells. A defect in RFXANK was first suggested by genetic complementation analyses, then assessed with the demonstration of a homozygous mutation affecting a splice donor site downstream exon 4 of RFXANK. Because the severe deletion of the resulting protein cannot account for the expression of certain HLA-D genes, minor alternative transcripts of the RFXANK gene were analyzed. We thereby showed the existence of a transcript lacking exon 4, encoding a 28-aa-deleted protein that retains a transcriptional activity. Altogether, we characterize a new type of mutation in the RFXANK gene in a MHC class II-defective patient leading to an uncoordinated expression of the HLA-D genes, and propose that this phenotype is ensured by severely limited amounts of an active, although truncated RFXANK protein.