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Uncoordinated HLA-D Gene Expression in a RFXANK-Defective Patient with MHC Class II Deficiency¹

Ana-Maria Lennon-Duménil^2,3,*, Mohamed-Ridha Barbouche^2,, Jocelyn Vedrenne^2,, Thomas Prod’Homme, Mohamed Béjaoui, Salma Ghariani, Dominique Charron, Marc Fellous^*, Koussay Dellagi and Catherine Alcaïde-Loridan^4,

^* Institut National de la Santé et de la Recherche Médicale Unité 276, Institut Pasteur, Paris, France; Laboratoire d’Immunologie, World Health Organization Collaborative Center for Research and Training in Immunology, Institut Pasteur de Tunis, Tunis, Tunisie, France; Institut National de la Santé et de la Recherche Médicale U396, Centre de Recherches Biomédicales des Cordeliers, Paris, France; and Centre de Greffe de Moelle Osseuse, Tunis, Tunisie, France

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 -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.