HGNC Approved Gene Symbol: RFX5
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:151,340,640-151,347,252 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q21.3 | Bare lymphocyte syndrome, type II, complementation group C | 209920 | Autosomal recessive | 3 |
| Bare lymphocyte syndrome, type II, complementation group E | 209920 | Autosomal recessive | 3 |
Major histocompatibility complex (MHC) class II molecules are heterodimeric transmembrane glycoproteins consisting of alpha and beta chains. In man, there are 3 MHC class II isotypes: HLA-DR, -DP, and -DQ. MHC class II molecules play a key role in the immune system. They present exogenous antigenic peptides to the receptor of CD4+ T-helper lymphocytes, thereby triggering the antigen-specific T-cell activation events required for the initiation and sustenance of immune responses. Durand et al. (1997) noted that the crucial role in the control of the immune response is exemplified by the finding that ectopic or aberrantly high levels of MHC class II expression is associated with autoimmune diseases, while a lack of MHC class II expression results in a severe immunodeficiency syndrome called MHC class II deficiency, or the bare lymphocyte syndrome type II (BLS; 209920). At least 4 complementation groups have been identified in B-cell lines established from patients with BLS. The molecular defect responsible for complementation group A resides in the gene encoding CIITA (MHC2TA; 600005). CIITA is a non-DNA-binding transactivator that functions as a molecular switch controlling both cell-type-specific and inducible MHC class II gene transcription. In contrast, the defects in complementation groups B, C, and D all lead to a deficiency in RFX, a nuclear protein complex that binds to the X box of MHC class II promoters (see RFX2; 142765). The lack of RFX binding activity in complementation group C results from mutations in the gene encoding the 75-kD subunit of RFX (Steimle et al., 1995). This gene was called RFX5 because it is the fifth member of the growing family of DNA-binding proteins sharing a novel and highly characteristic DNA-binding domain called the RFX motif.
Two of the genes defective in the 5 complementation groups identified in class II-negative bare lymphocyte syndrome or in corresponding laboratory mutants have been cloned (Mach et al., 1996). One gene encodes RFX5; the other, MHC2TA (CIITA), encodes a large protein with a defined acidic transcriptional activation domain. The latter protein does not interact with DNA. Scholl et al. (1997) demonstrated that RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II MHC promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA.
Nekrep et al. (2000) demonstrated a direct interaction between the C terminus of RFXAP (601861) and RFXANK (603200); mutant RFXAP or RFXANK proteins failed to bind. The authors found that RFX5 binds only to the RFXANK-RFXAP scaffold and not to either protein alone. However, neither the scaffold nor RFX5 alone can bind DNA. Nekrep et al. (2000) concluded that the binding of the RFXANK-RFXAP scaffold to RFX5 leads to a conformational change in the latter that exposes the DNA-binding domain of RFX5. The DNA-binding domain of RFX5 anchors the RFX complex to MHC class II X and S promoter boxes. Another part of the RFX5 protein interacts with MHC2TA. The authors pointed out that mutation of either protein in complementation group B or group D of BLS patients prevents its binding to the other protein, explaining why MHC class II promoters are bare in the bare lymphocyte syndrome.
Emery et al. (1996) reviewed RFX1, RFX5, and other members of the RFX family of DNA-binding proteins.
Villard et al. (1997) mapped the RFX5 gene to chromosome 1q21 by fluorescence in situ hybridization.
Villard et al. (1997) characterized the mutations in 4 patients with MHC class II deficiency known to harbor a defect in the RFX5 gene.
Hosts and pathogens evolve various responses for controlling infection and evading destruction, respectively. Using column chromatography, Zhong et al. (2001) identified a factor in Chlamydia trachomatis, the causative organism of trachoma and chronic urogenital infection, that degrades the transcription factors RFX5 and USF1 (191523). The degradation of these host factors correlates with the suppression of MHC class I and class II antigen expression in infected cells, thereby suppressing the host immune response.
Nekrep et al. (2002) identified an arg149-to-gln mutation (R149Q; 601863.0005) in the DNA-binding domain of RFX5 (residues 92 to 168) in cell lines (termed 'Ker' cell lines) derived from the histoidentical twins lacking MHC class II transcription reported by Wolf et al. (1995) and Douhan et al. (1996). Functional and structural modeling analyses indicated that the mutant protein was incapable of binding the X box of the HLA-DRA (142860) promoter, whereas expression of wildtype RFX5 in the Ker cell lines rescued MHC class II expression.
In 2 sibs, identified as THF and EDF, with bare lymphocyte syndrome type II, complementation group C (209920), Villard et al. (1997) demonstrated a 10-nucleotide deletion involving nucleotides 259-268 in the RFX5 gene upstream of the DNA-binding domain region. The deletion led to a frameshift followed by an out-of-frame stop codon situated 66 nucleotides downstream. Only the deleted form of RFX5 mRNA was present in these sibs. Studies of genomic DNA demonstrated that the 10-nucleotide deletion resulted from a point mutation in a splice donor site. The primary mutation was the G-to-A transition at position +5 in the splice donor site situated 3-prime of exon 2. This resulted in the use of a cryptic splice donor site situated 10 nucleotides upstream in exon 2 and hence in the excision of the last 10 nucleotides of exon 2 from the mRNA. Both parents were heterozygous for the mutation.
In a patient identified as Ro, with bare lymphocyte syndrome type II, complementation group C (209920), Steimle et al. (1995) demonstrated and Villard et al. (1997) confirmed the presence of a point mutation at nucleotide 1032 converting an arginine codon (CGA) to a premature stop codon (TGA). Villard et al. (1997) demonstrated that the patient was homozygous for the mutated allele, whereas both parents were heterozygous.
In a patient identified as SJO, with bare lymphocyte syndrome type II, complementation group C (209920), Villard et al. (1997) identified compound heterozygosity of the RFX5 gene, one allele containing a G-to-A transition at position -1 resulting in the use of a cryptic splice acceptor site situated 5 nucleotides downstream in exon 5 and deletion of the first 5 nucleotides (386-390) of exon 5 from the mRNA. The precise mutation affecting the second RFX5 allele in SJO had not been defined; however, no intact mRNA derived from that allele was detectable in SJO (Steimle et al., 1995).
Peijnenburg et al. (1999) fused fibroblasts of a patient with bare lymphocyte syndrome type II, complementation group C (209920), with fibroblasts derived from patients representative of each of the 4 complementation groups. Transient heterokaryon analysis indicated that the patient belonged to complementation group C. Furthermore, transfection of wildtype RFX5 cDNA into the patient's fibroblasts resulted in correction of the defect. Mutation analysis revealed that the RFX5 mRNA lacked 4 nucleotides and that this deletion was a consequence of a G-to-A transition in a splice acceptor site. The patient was found to be homozygous for the splice site mutation. The nucleotides deleted were CAAG at positions 312-315 of the RFX5 cDNA. The deletion led to a frameshift and an out of frame stop codon located at nucleotides 403-405 of the wildtype RFX5 cDNA sequence. As a result, the mutated RFX5 mRNA encoded a truncated protein of 82 amino acids which lacked the DNA binding domain (DBD). The presence of the G-to-A point mutation and the use of a cryptic splice acceptor site (aCAAG) apparently resulted in an RFX5 mRNA from which 4 nucleotides of the particular exon were spliced out. Both parents were heterozygous for the mutation.
In cell lines derived from histochemical twins with the putative fifth bare lymphocyte syndrome complementation group (209920), Nekrep et al. (2002) identified a G-to-A transition at nucleotide 446 of the RFX5 gene, resulting in an arg149-to-gln (R149Q) mutation in the DNA-binding domain.
Douhan, J., III, Hauber, I., Eibl, M. M., Glimcher, L. H. Genetic evidence for a new type of major histocompatibility complex class II combined immunodeficiency characterized by a dyscoordinate regulation of HLA-D alpha and beta chains. J. Exp. Med. 183: 1063-1069, 1996. [PubMed: 8642248] [Full Text: https://doi.org/10.1084/jem.183.3.1063]
Durand, B., Sperisen, P., Emery, P., Barras, E., Zufferey, M., Mach, B., Reith, W. RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. EMBO J. 16: 1045-1055, 1997. [PubMed: 9118943] [Full Text: https://doi.org/10.1093/emboj/16.5.1045]
Emery, P., Durand, B., Mach, B., Reith, W. RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom. Nucleic Acids Res. 24: 803-807, 1996. [PubMed: 8600444] [Full Text: https://doi.org/10.1093/nar/24.5.803]
Mach, B., Steimle, V., Martinez-Soria, E., Reith, W. Regulation of MHC class II genes: lessons from a disease. Annu. Rev. Immun. 14: 301-331, 1996. [PubMed: 8717517] [Full Text: https://doi.org/10.1146/annurev.immunol.14.1.301]
Nekrep, N., Jabrane-Ferrat, N., Peterlin, B. M. Mutations in the bare lymphocyte syndrome define critical steps in the assembly of the regulatory factor X complex. Molec. Cell Biol. 20: 4455-4461, 2000. [PubMed: 10825209] [Full Text: https://doi.org/10.1128/MCB.20.12.4455-4461.2000]
Nekrep, N., Jabrane-Ferrat, N., Wolf, H. M., Eibl, M. M., Geyer, M., Peterlin, B. M. Mutation in a winged-helix DNA-binding motif causes atypical bare lymphocyte syndrome. Nature Immun. 3: 1075-1081, 2002. [PubMed: 12368908] [Full Text: https://doi.org/10.1038/ni840]
Peijnenburg, A., Van Eggermond, M. C. J. A., Van den Berg, R., Sanal, O., Vossen, J. M. J. J., Van den Elsen, P. J. Molecular analysis of an MHC class II deficiency patient reveals a novel mutation in the RFX5 gene. Immunogenetics 49: 338-345, 1999. [PubMed: 10079298] [Full Text: https://doi.org/10.1007/s002510050501]
Scholl, T., Mahanta, S. K., Strominger, J. L. Specific complex formation between the type II bare lymphocyte syndrome-associated transactivators CIITA and RFX5. Proc. Nat. Acad. Sci. 94: 6330-6334, 1997. [PubMed: 9177217] [Full Text: https://doi.org/10.1073/pnas.94.12.6330]
Steimle, V., Durand, B., Barras, E., Zuffrey, M., Hadam, M. R., Mach, B., Reith, W. A novel DNA binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev. 9: 1021-1032, 1995. [PubMed: 7744245] [Full Text: https://doi.org/10.1101/gad.9.9.1021]
Villard, J., Reith, W., Barras, E., Gos, A., Morris, M. A., Antonarakis, S. E., Van den Elsen, P. J., Mach, B. Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a novel transcription factor affected in major histocompatibility complex class II deficiency. Hum. Mutat. 10: 430-435, 1997. [PubMed: 9401005] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)10:6<430::AID-HUMU3>3.0.CO;2-H]
Wolf, H. M., Hauber, I., Gulle, H., Thon, V., Eggenbauer, H., Fischer, M. B., Fiala, S., Eibl, M. M. Brief report: Twin boys with major histocompatibility complex class II deficiency but inducible immune responses. New Eng. J. Med. 332: 86-90, 1995. [PubMed: 7990905] [Full Text: https://doi.org/10.1056/NEJM199501123320204]
Zhong, G., Fan, P., Ji, H., Dong, F., Huang, Y. Identification of a chlamydial protease-like activity factor responsible for the degradation of host transcription factors. J. Exp. Med. 193: 935-942, 2001. [PubMed: 11304554] [Full Text: https://doi.org/10.1084/jem.193.8.935]