ABSTRACT
Type III bare lymphocyte syndrome (BLS) is a severe combined immunodeficiency disease caused by the absence of MHC Class II expression associated with low expression of class I molecules. Here, we report a case with type III BLS who lacked RFXAP (Regulatory factor X-associated protein) expression as a result from a novel mutation introducing a premature stopcodon in DE-region at amino acid 73.
Subject(s)
Mutation , Severe Combined Immunodeficiency/genetics , Transcription Factors/genetics , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Codon, Nonsense/genetics , Female , Genetic Association Studies , Homozygote , Humans , Infant , Lymphocyte Count , Severe Combined Immunodeficiency/metabolism , Transcription Factors/metabolismABSTRACT
MHC class II deficiency patients are mutated for transcription factors that regulate the expression of major histocompatibility complex (MHC) class II genes. Four complementation groups (A-D) are defined and the gene defective in group A has been shown to encode the MHC class II transactivator (CIITA). Here, we report the molecular characterization of a new MHC class II deficiency patient, ATU. Cell fusion experiments indicated that ATU belongs to complementation group A. Subsequent mutation analysis revealed that the CIITA mRNA lacked 84 nucleotides. This deletion was the result of the absence of a splice donor site in the CIITA gene of ATU. As a result of this novel homozygous genomic deletion, ATU CIITA failed to transactivate MHC class II genes. Furthermore, this truncated CIITA of ATU did not display a dominant negative effect on CIITA-mediated transactivation of various isotypic MHC class II promoters.
Subject(s)
Gene Expression/genetics , Genes, MHC Class II/genetics , Nuclear Proteins , RNA Splicing/genetics , Sequence Deletion/genetics , Trans-Activators/genetics , Antigens, Differentiation, B-Lymphocyte/genetics , Base Sequence , Cell Fusion , Cell Line, Transformed , Exons/genetics , Fibroblasts , Gene Expression/drug effects , Genes, MHC Class I/genetics , Genes, MHC Class II/immunology , Genetic Complementation Test , Histocompatibility Antigens Class II/genetics , Homozygote , Humans , Interferon-gamma/pharmacology , Leucine/genetics , Phenotype , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Trans-Activators/chemistry , Transcriptional Activation/drug effects , Transcriptional Activation/genetics , beta 2-Microglobulin/geneticsABSTRACT
MHC class II deficiency or bare lymphocyte syndrome is a severe combined immunodeficiency caused by defects in MHC-specific transcription factors. In the present study, we show that fibroblasts derived from a recently identified bare lymphocyte syndrome patient, SSI, were mutated for RFX5, one of the DNA-binding components of the RFX complex. Despite the lack of functional RFX5 and resulting MHC class II-deficient phenotype, transfection of exogenous class II transactivator (CIITA) in these fibroblasts can overcome this defect, resulting in the expression of HLA-DR, but not of DP, DQ, and invariant chain. The lack of invariant chain expression correlated with lack of CIITA-mediated transactivation of the invariant chain promoter in transient transfection assays in SSI fibroblast cells. Consequently, these CIITA transfectants lacked Ag-presenting functions.
